This application claims the priority of U.S. Provisional Application No. 62/150,731, filed Apr. 21, 2015, the contents of which are hereby incorporated by reference.
Throughout this application various publications are referenced. The disclosures of these publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.
BACKGROUND OF THE INVENTION Multiple Sclerosis Multiple sclerosis (MS) is a chronic, debilitating autoimmune disease of the central nervous system (CNS) with either relapsing-remitting (RR) or progressive course leading to neurologic deterioration and disability. At time of initial diagnosis, RRMS is the most common form of the disease (1) which is characterized by unpredictable acute episodes of neurological dysfunction (relapses), followed by variable recovery and periods of clinical stability. The vast majority of RRMS patients eventually develop secondary progressive (SP) disease with or without superimposed relapses. Around 15% of patients develop a sustained deterioration of their neurological function from the beginning; this form is called primary progressive (PP) MS. Patients who have experienced a single clinical event (Clinically Isolated Syndrome or “CIS”) and who show lesion dissemination on subsequent magnetic resonance imaging (MRI) scans according to McDonald's criteria, are also considered as having relapsing MS.(2)
With a prevalence that varies considerably around the world, MS is the most common cause of chronic neurological disability in young adults.(3, 4) Anderson et al. estimated that there were about 350,000 physician-diagnosed patients with MS in the United States in 1990 (approx. 140 per 100,000 population).(5) It is estimated that about 2.5 million individuals are affected worldwide.(6) In general, there has been a trend toward an increasing prevalence and incidence of MS worldwide, but the reasons for this trend are not fully understood.(5)
Current therapeutic approaches consist of i) symptomatic treatment ii) treatment of acute relapses with corticosteroids and iii) treatment aimed to modify the course of the disease. Currently approved therapies target the inflammatory processes of the disease. Most of them are considered to act as immunomodulators but their mechanisms of action have not been completely elucidated. Immunosuppressants or cytotoxic agents are also used in some patients after failure of conventional therapies. Several medications have been approved and clinically ascertained as efficacious for the treatment of RR-MS; including BETASERON®, AVONEX® and REBIF®, which are derivatives of the cytokine interferon beta (IFNB), whose mechanism of action in MS is generally attributed to its immunomodulatory effects, antagonizing pro-inflammatory reactions and inducing suppressor cells.(7) Other approved drugs for the treatment of MS include Mitoxantrone and Natalizumab.
Glatiramer Acetate Glatiramer acetate (GA) is the active substance in Copaxone®, a marketed product indicated for reduction of the frequency of relapses in patients with RRMS. Its effectiveness in reducing relapse rate and disability accumulation in RR-MS is comparable to that of other available immunomodulating treatments.(8, 9, 10) Glatiramer acetate consists of the acetate salts of synthetic polypeptides containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine and L-lysine. The average molecular weight of glatiramer acetate is between 5,000 and 9,000 Daltons. At a daily standard dose of 20 mg, GA is generally well tolerated, however response to the drug is variable. In various clinical trials, GA reduced relapse rates and progression of disability in patients with RR-MS. The therapeutic effect of GA is supported by the results of magnetic resonance imaging (MRI) findings from various clinical centers (11), however there are no validated predictive biomarkers of response to GA treatment.
A possible initial mode of action of GA is associated with binding to MHC molecules and consequent competition with various myelin antigens for their presentation to T cells.(12) A further aspect of its mode of action is the potent induction of T helper 2 (Th2) type cells that presumably can migrate to the brain and lead to in situ bystander suppression.(13) It has been shown that GA treatment in MS results in the induction of GA-specific T cells with predominant Th2 phenotype both in response to GA and cross-reactive myelin antigens.(13, 14) Furthermore, the ability of GA-specific infiltrating cells to express anti-inflammatory cytokines such as IL-10 and transforming growth factor-beta (TGF-β) together with brain-derived neurotrophic factor (BDNF) seem to correlate with the therapeutic activity of GA in EAE.(15, 16, 17)
Clinical experience with GA consists of information obtained from completed and ongoing clinical trials and from post-marketing experience. The clinical program includes three double-blind, placebo-controlled studies in RRMS subjects treated with GA 20 mg/day.(18, 19, 20) A significant reduction in the number of relapses, compared with placebo, was seen. In the largest controlled study, the relapse rate was reduced by 32% from 1.98 under placebo to 1.34 under GA 20 mg. GA 20 mg has also demonstrated beneficial effects over placebo on MRI parameters relevant to RRMS. A significant effect in median cumulative number of Gd-enhancing lesions over 9 months of treatment (11 lesions in the 20 mg group compared to 17 lesions under placebo) was demonstrated.
The clinical program with GA also includes one double-blind study in chronic-progressive MS subjects,(21) one double-blind placebo-controlled study in primary progressive patients, (22) one double-blind placebo-controlled study in CIS patients(23) and numerous open-label and compassionate use studies, mostly in RRMS. The clinical use of GA has been extensively reviewed and published in the current literature (24, 25, 26, 27).
U.S. Pat. No. 7,855,176 discloses administering glatiramer acetate to patients afflicted with relapsing-remitting multiple sclerosis (RRMS) by subcutaneous injection of 0.5 ml of an aqueous pharmaceutical solution which contains in solution 20 mg glatiramer acetate and 20 mg mannitol (34).
U.S. Patent Application Publication No. US 2011-0046065 A1 discloses administering glatiramer acetate to patients suffering from relapsing-remitting multiple sclerosis by three subcutaneous injections of a therapeutically effective dose of glatiramer acetate over a period of seven days with at least one day between every subcutaneous injection (35).
Pharmacogenomics Pharmacogenomics is the methodology which associates genetic variability with physiological responses to drug. Pharmacogenetics is a subset of pharmacogenomics and is defined as “the study of variations in DNA sequence as related to drug response” (ICH E15; fda.gov/downloads/RegulatoryInformation/Guidances/ucm129296.pdf. Pharmacogenetics focuses on genetic polymorphism in genes related to drug metabolism, drug mechanism of action, disease type, and side effects. Pharmacogenetics is the cornerstone of Personalized Medicine which allows the development of more individualized drug therapies to obtain more effective and safe treatment.
Pharmacogenetics has become a core component of many drug development programs, being used to explain variability in drug response among subjects in clinical trials, to address unexpected emerging clinical issues, such as adverse events, to determine eligibility for a clinical trial (pre-screening) to optimize trial yield, to develop drug-linked diagnostic tests to identify patients who are more likely or less likely to benefit from treatment or who may be at risk of adverse events, to provide information in drug labels to guide physician treatment decisions, to better understand the mechanism of action or metabolism of new and existing drugs, and to provide better understanding of disease mechanisms.
Generally, Pharmacogenetics analyses are performed in either of two methodology approaches: Candidate genes research technique, and Genome Wide Association Study (GWAS). Candidate genes research technique is based on the detection of polymorphism in candidate genes pre-selected using the knowledge on the disease, the drug mode of action, toxicology or metabolism of drug. The Genome Wide Association Study (GWAS) enables the detection of more than 1 M (one million) polymorphisms across the genome. This approach is used when related genes are unknown. DNA arrays used for GWAS can be also analyzed per gene as in candidate gene approach.
Pharmacogenetic Studies Various pharmacogenetic studies were done in MS patients. For example, a Genome-Wide Association study by Byun et al. (36) focused on extreme clinical phenotypes in order to maximize the ability to detect genetic differences between responders and non-responders to interferon-beta. A multi-analytical approach detected significant associations between several SNPs and treatment response. Responders and Non-Responders had significantly different genotype frequencies for SNPs located in many genes, including glypican 5, collagen type XXV α1, hyaluronan proteoglycan link protein, calpastatin, and neuronal PAS domain protein 3. Other studies used pharmacogenetic analyses in order to characterize the genomic profile and gene expression profile of IFN responders and non-responders.
Other pharmacogenetic studies analyzed the genetic background associated with response to Glatiramer Acetate. For examples, Fusco C et al (37) assessed a possible relationship between HLA alleles and response to GA (N=83 BRMS). DRB1*1501 allele frequency was increased in MS patients compared to healthy controls (10.8% vs 2.7%; p=0.001). In DRB1*1501 carriers the response rate was 81.8% compared to 39.4% in non-carriers of DRB1*1501 and to 50% in the whole study population. Grossman et al (38) genotyped HLA-DRB1*1501 and 61 SNPs within a total of 27 other candidate genes, on DNA from two clinical trial cohorts. The study revealed no association between HLA-DRB1*1501 and response to GA. The results of the study are disclosed in the international application published as WO2006/116602 (39).
Pharmacogenetics is the cornerstone of personalized medicine which allows the development of more individualized drug therapies to obtain more effective and safe treatment. Multiple Sclerosis is a complex disease with clinical heterogeneity. In patients afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis, the ability to determine the likelihood of treatment success would be an important tool improving the therapeutic management of the patients. As the therapeutic options for MS and CIS increase, the importance of being able to determine who will respond favorably to therapy and specifically to GA, has become of increasing significance.
SUMMARY OF THE INVENTION Independent Embodiments The present invention provides a method for treating a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis with a pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier, comprising the steps of:
(i) determining a genotype of the subject at a location corresponding to the location of one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of: rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458,
(ii) identifying the subject as a predicted responder to glatiramer acetate if the genotype of the subject contains
one or more A alleles at the location of kgp8110667, rs10162089, rs759458 and kgp6214351, or
one or more G alleles at the location of kgp24415534, kgp6599438, kgp7747883, kgp8817856, rs16886004 and rs1894408; and
(iii) administering the pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier to the subject only if the subject is identified as a predicted responder to glatiramer acetate.
The present also invention provides a method of identifying a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis as a predicted responder or as a predicted non-responder to glatiramer acetate, the method comprising determining the genotype of the subject at a location corresponding to the location of one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458, and
identifying the human subject as a predicted responder to glatiramer acetate if the genotype of the subject contains
one or more A alleles at the location of kgp8110667, rs10162089, rs759458 and kgp6214351, or
one or more G alleles at the location of kgp24415534, kgp6599438, kgp7747883, kgp8817856, rs16886004 and rs1894408,
or identifying the human subject as a predicted non-responder to glatiramer acetate if the genotype of the subject contains
no A alleles at the location of kgp8110667, rs10162089, rs759458 and kgp6214351, or
no G alleles at the location of kgp24415534, kgp6599438, kgp7747883, kgp8817856, rs16886004 and rs1894408.
The present invention also provides a kit for identifying a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis as a predicted responder or as a predicted non-responder to glatiramer acetate, the kit comprising at least one probe specific for the location of a SNP selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
The present invention also provides a kit for identifying a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis as a predicted responder or as a predicted non-responder to glatiramer acetate, the kit comprising at least one pair of PCR primers designed to amplify a DNA segment which includes the location of a SNP selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
The present invention also provides a kit for identifying a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis as a predicted responder or as a predicted non-responder to glatiramer acetate, the kit comprising a reagent for performing a method selected from the group consisting of restriction fragment length polymorphism (RFLP) analysis, sequencing, single strand conformation polymorphism analysis (SSCP), chemical cleavage of mismatch (CCM), gene chip and denaturing high performance liquid chromatography (DHPLC) for determining the genotype of the subject at a location corresponding to the location of at least one SNP selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
The present invention also provides a kit for identifying a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis as a predicted responder or as a predicted non-responder to glatiramer acetate, the kit comprising reagents for TaqMan Open Array assay designed for determining the genotype of the subject at a location corresponding to the location of at least one SNP selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
The present invention also provides a kit for identifying a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis as a predicted responder or as a predicted non-responder to glatiramer acetate, the kit comprising
a) at least one probe specific for a location corresponding to the location of at least one SNP;
b) at least one pair of PCR primers designed to amplify a DNA segment which includes a location corresponding to the location of at least one SNP;
c) at least one pair of PCR primers designed to amplify a DNA segment which includes a location corresponding to the location of at least one SNP and at least one probe specific for a location corresponding to the location of at least one SNP;
d) a reagent for performing a method selected from the group consisting of restriction fragment length polymorphism (RELP) analysis, sequencing, single strand conformation polymorphism analysis (SSCP), chemical cleavage of mismatch (CCM), gene chip and denaturing high performance liquid chromatography (DHPLC) for determining the identity of at least one SNP; or
e) reagents for TaqMan Open Array assay designed for determining the genotype at a location corresponding to the location of at least one SNP,
wherein the at least one SNP is selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
The present invention also provides a probe for identifying the genotype of a location corresponding to the location of a SNP selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
The present invention also provides Glatiramer acetate or a pharmaceutical composition comprising glatiramer acetate for use in treating a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis which human subject is identified as a predicted responder to glatiramer acetate by:
a) determining a genotype of the subject at a location corresponding to the location of one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of: rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458, and
b) identifying the subject as a predicted responder to glatiramer acetate if the genotype of the subject contains
one or more A alleles at the location of kgp8110667, rs10162089, rs759458 and kgp6214351, or
one or more G alleles at the location of kgp24415534, kgp6599438, kgp7747883, kgp8817856, rs16886004 and rs1894408.
The present invention also provides a method of determining the genotype of a human subject comprising identifying whether the genotype of a human subject contains
one or more A alleles at the location of kgp8110667, rs10162089, rs759458 and kgp6214351, or
one or more G alleles at the location of kgp24415534, kgp6599438, kgp7747883, kgp8817856, rs16886004 and rs1894408.
BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows Receiver Operating Characteristics for optimization of test threshold.
FIG. 2 shows Response Rate of Predicted Responders (green line) and Response Rate of Predicted Non-Responders (red line) by predictive test threshold.
FIG. 3 shows overall percent of Predicted Responders by predictive test threshold.
FIG. 4 shows chi square P-values (−Log P-value) of different test thresholds in the ability of the test to differentiate between cases and controls. A threshold of 0.71 demonstrated the most significant p-value.
FIG. 5 shows overall Response to glatiramer acetate as Predicted by Model (model 3, threshold 0.71) for Predicted Responders (left panel) and Predicted Non-Responders (right panel).
FIG. 6 shows GALA and FORTE patients were stratified by clearly defined response. High Response: improved ARR (ARR change <(−1), during study versus prior 2 years). Low Response: no change or worsening of ARR (ARR change ≧0, during study versus previous 2 years).
FIG. 7 shows predictive model building for GALA and FORTE cohorts.
FIG. 8 shows the algorithm and calculation of values for all genotyped patients of the GALA and FORTE cohorts, based on the predictive model (11 SNPs and 2 clinical variables).
FIG. 9 shows the algorithm and calculation of values for all genotyped patients of the GALA and FORTE cohorts, based on the 11 SNPs in the predictive model, without including the clinical variables, and using a threshold at ˜30% of the population classified as “predicted responders”.
FIG. 10 shows the algorithm and calculation of values for all genotyped patients of the GALA and FORTE cohorts based on the 11 SNPs in the predictive model, without including the clinical variables.
FIG. 11 shows the algorithm and calculation of values for all genotyped patients of the GALA and FORTE cohorts based on the 10 SNPs in the predictive model, without including the clinical variables
FIG. 12 shows the algorithm and calculation of values for all genotyped patients of the GALA and FORTE cohorts based on the 9 SNPs in the predictive model, without including the clinical variables
FIG. 13 shows the algorithm and calculation of values for all genotyped patients of the GALA and FORTE cohorts, based on the 10 SNPs in the predictive model, without including the clinical variables, and using a threshold at ˜30% of the population classified as “predicted responders”.
FIG. 14 shows the algorithm and calculation of values for all genotyped patients of the GALA and FORTE cohorts, based on the 9 SNPs in the predictive model, without including the clinical variables, and using a threshold at ˜30% of the population classified as “predicted responders”.
DETAILED DESCRIPTION OF THE INVENTION Embodiments of the Invention The present invention provides a method for treating a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis with a pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier, comprising the steps of:
(i) determining a genotype of the subject at a location corresponding to the location of one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of: rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458,
(ii) identifying the subject as a predicted responder to glatiramer acetate if the genotype of the subject contains
one or more A alleles at the location of kgp8110667, rs10162089, rs759458 and kgp6214351, or
one or more G alleles at the location of kgp24415534, kgp6599438, kgp7747883, kgp8817856, rs16886004 and rs1894408; and
(iii) administering the pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier to the subject only if the subject is identified as a predicted responder to glatiramer acetate.
In some embodiments, step (i) further comprises determining a genotype of the subject at a location corresponding to the location of one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of: rs10988087, rs1573706, rs17575455, rs2487896, rs3135391, rs6097802 and rs947603, and wherein step (ii) further comprises identifying the subject as a predicted responder to glatiramer acetate if the genotype of the subject contains one or more A alleles at the location of rs10988087, one or more C alleles at the location of rs17575455, or one or more G alleles at the location of rs1573706, rs2487896, rs3135391, rs6097801 or rs947603.
In some embodiments, administering the pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier comprises administering to the human subject three subcutaneous injections of the pharmaceutical composition over a period of seven days with at least one day between every subcutaneous injection.
In some embodiments, the pharmaceutical composition is a unit dose of a 1 ml aqueous solution comprising 40 mg of glatiramer acetate.
In some embodiments, wherein the pharmaceutical composition is a unit dose of a 1 ml aqueous solution comprising 20 mg of glatiramer acetate.
In some embodiments, wherein the pharmaceutical composition is a unit dose of a 0.5 ml aqueous solution comprising 20 mg of glatiramer acetate.
In some embodiments, wherein the pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier is administered as a monotherapy.
In some embodiments, wherein the pharmaceutical composition comprising glatiramer acetate and a pharmaceutically acceptable carrier is administered in combination with at least one other multiple sclerosis drug.
The present also invention provides a method of identifying a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis as a predicted responder or as a predicted non-responder to glatiramer acetate, the method comprising determining the genotype of the subject at a location corresponding to the location of one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458, and identifying the human subject as a predicted responder to glatiramer acetate if the genotype of the subject contains
one or more A alleles at the location of kgp8110667, rs10162089, rs759458 and kgp6214351, or
one or more G alleles at the location of kgp24415534, kgp6599438, kgp7747883, kgp8817856, rs16886004 and rs1894408,
or identifying the human subject as a predicted non-responder to glatiramer acetate if the genotype of the subject contains
no A alleles at the location of kgp8110667, rs10162089, rs759458 and kgp6214351, or
no G alleles at the location of kgp24415534, kgp6599438, kgp7747883, kgp8817856, rs16886004 and rs1894408.
In some embodiments, the invention further comprises determining a genotype of the subject at a location corresponding to the location of one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of: rs10988087, rs1573706, rs17575455, rs2487896, rs3135391, rs6097801 and rs947603, and
identifying the human subject as a predicted responder to glatiramer acetate if the genotype of the subject contains one or more A alleles at the location of rs10988087, one or more C alleles at the location of rs17575455, or one or more G alleles at the location of rs1573706, rs2487896, rs3135391, rs6097801 or rs947603, or
identifying the human subject as a predicted non-responder to glatiramer acetate if the genotype of the subject contains no A alleles at the location of rs10988087, no C alleles at the location of rs17575455, or no G alleles at the location of rs1573706, rs2487896, rs3135391, rs6097801 or rs947603.
In some embodiments, the genotype is determined from a nucleic acid-containing sample that has been obtained from the subject.
In some embodiments, determining the genotype comprises using a method selected from the group consisting of restriction fragment length polymorphism (RFLP) analysis, sequencing, single strand conformation polymorphism analysis (SSCP), chemical cleavage of mismatch (CCM), denaturing high performance liquid chromatography (DHPLC), Polymerase Chain Reaction (PCR) and an array, or a combination thereof.
In some embodiments, the genotype is determined using at least one pair of PCR primers and at least one probe.
In some embodiments, the array is selected from the group consisting of a gene chip, and a TaqMan Open Array.
In some embodiments, the gene chip is selected from the group consisting of a DNA array, a DNA microarray, a DNA chip, and a whole genome genotyping array.
In some embodiments, the array is a TaqMan Open Array.
In some embodiments, the gene chip is a whole genome genotyping array.
In some embodiments, determining the genotype of the subject at the location corresponding to the location of the said one or more SNPs comprises:
(i) obtaining DNA from a sample that has been obtained from the subject;
(ii) optionally amplifying the DNA; and
(iii) subjecting the DNA or the amplified DNA to a method selected from the group consisting of restriction fragment length polymorphism (RFLP) analysis, sequencing, single strand conformation polymorphism analysis (SSCP), chemical cleavage of mismatch (CCM), denaturing high performance liquid chromatography (DHPLC), Polymerase Chain Reaction (PCR) and an array, or a combination thereof, for determining the identity the one or more SNPs.
In some embodiments, the array comprises a plurality of probes suitable for determining the identity of the one or more SNPs.
In some embodiments, the array is a gene chip.
In some embodiments, the gene chip is a whole genome genotyping array.
In some embodiments, the human subject is a naïve patient.
In some embodiments, the human subject has been previously administered glatiramer acetate.
In some embodiments, the human subject has been previously administered a multiple sclerosis drug other than glatiramer acetate.
In some embodiments, the genotype is determined at locations corresponding to the locations of 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 or more single nucleotide polymorphisms (SNPs).
In some embodiments, the genotype of the subject at the location corresponding to the location of one or more of the SNPs is determined indirectly by determining the genotype of the subject at a location corresponding to the location of at least one SNP that is in linkage disequilibrium with the one or more SNPs.
In some embodiments, the genotype of the subject at the location corresponding to the location of the one or more SNPs is determined by indirect genotyping.
In some embodiments, the indirect genotyping allows identification of the genotype of the subject at the location corresponding to the location of the one or more SNPs with a probability of at least 85%.
In some embodiments, the indirect genotyping allows identification of the genotype of the subject at the location corresponding to the location of the one or more SNPs with a probability of at least 90%.
In some embodiments, the indirect genotyping allows identification of the genotype of the subject at the location corresponding to the location of the one or more SNPs with a probability of at least 99%.
In some embodiments, the invention further comprises the step of determining the log number of relapses in the last two years for the human subject.
In some embodiments, the invention further comprises the step of determining the baseline Expanded Disability Status Scale (EDSS) score for the human subject.
In some embodiments, the invention further comprises applying the algorithm depicted in FIG. 11 or FIG. 13 to identify the subject as a predicted responder or as a predicted non-responder to glatiramer acetate.
In some embodiments, the step of determining the genotype further comprises determining a genotype of the subject at a location corresponding to the location of a single nucleotide polymorphism rs3135391;
wherein the step of identifying the human subject as a predicted responder to glatiramer acetate if the genotype of the subject further contains one or more G alleles at the location of rs3135391, or
wherein the step of identifying the human subject as a predicted non-responder to glatiramer acetate if the genotype of the subject further does not contain G alleles at the location of rs3135391; and
further comprising applying the algorithm depicted in FIG. 8, FIG. 9 or FIG. 10 to identify the subject as a predicted responder or as a predicted non-responder to glatiramer acetate.
In some embodiments, the location of a SNP selected from the group consisting of rs3135391, rs1894408, kpg6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
In some embodiments, the location of a SNP selected from the group consisting of kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
In some embodiments, the invention further comprises applying the algorithm depicted in FIG. 12 or FIG. 14 to identify the subject as a predicted responder or as a predicted non-responder to glatiramer acetate.
In some embodiments, the invention further comprises determining the genotype of the subject at a location corresponding to the location of one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of: kgp10148554, kgp10215554, kgp10762962, kgp10836214, kgp10989246, kgp11285883, kgp11604017, kgp11755256, kgp1211163, kgp12253568, kgp12562255, kgp1432800, kgp1682126, kgp1758575, kgp2176915, kgp22839559, kgp24521552, kgp2877482, kgp2920925, kgp2993366, kgp3188, kgp3287349, kgp3420309, kgp3488270, kgp3598966, kgp3624014, kgp3697615, kgp394638, kgp4037661, kgp4137144, kgp433351, kgp4456934, kgp4575797, kgp4591145, kgp4892427, kgp4970670, kgp4985243, kgp5252824, kgp5326762, kgp541892, kgp5691690, kgp5747456, kgp5894351, kgp5924341, kgp5949515, kgp6042557, kgp6081880, kgp6194428, kgp6213972, kgp625941, kgp6301155, kgp6429231, kgp6828277, kgp6889327, kgp6990559, kgp7006201, kgp7151153, kgp7161038, kgp7653470, kgp7778345, kgp7932108, kgp8145845, kgp8644305, kgp8847137, kgp9143704, kgp9409440, kgp956070, kgp9909702, kgp9927782, rs10038844, rs1026894, rs10495115, rs11562998, rs11563025, rs11750747, rs11947777, rs12043743, rs12233980, rs12341716, rs12472695, rs12881439, rs13168893, rs13386874, rs1357718, rs1393037, rs1393040, rs1397481, rs1474226, rs1508515, rs1534647, rs16846161, rs1715441, rs17187123, rs17245674, rs17419416, rs1793174, rs1883448, rs1905248, rs209568, rs2354380, rs2618065, rs263247, rs2662, rs28993969, rs34647183, rs35615951, rs3768769, rs3847233, rs3858034, rs3858035, rs3858036, rs3858038, rs3894712, rs4740708, rs4797764, rs4978567, rs528065, rs6459418, rs6577395, rs6811337, rs7119480, rs7123506, rs7231366, rs7680970, rs7684006, rs7696391, rs7698655, rs7819949, rs7846783, rs7949751, rs7961005, rs8000689, rs8018807, rs961090, rs967616, rs9948620 and rs9953274, and
identifying the human subject as a predicted responder to glatiramer acetate if the genotype of the subject contains
one or more A alleles at the location of kgp10762962, kgp11285883, kgp11604017, kgp1211163, kgp12253568, kgp12562255, kgp2176915, kgp24521552, kgp2877482, kgp2993366, kgp31.88, kgp3624014, kgp394638, kgp4037661, kgp433351, kgp4456934, kgp4575797, kgp4591145, kgp4892427, kgp4970670, kgp4985243, kgp5252824, kgp5326762, kgp541892, kgp5747456, kgp5894351, kgp6042557, kgp6081880, kgp6194428, kgp6429231, kgp7006201, kgp7151153, kgp7161038, kgp7653470, kgp8145845, kgp8644305, kgp9143704, kgp9409440, kgp9909702, kgp9927782, rs10038844, rs10495115, rs11750747, rs12341716, rs12881439, rs13168893, rs1393040, rs1474226, rs1534647, rs1715441, rs17187123, rs17245674, rs17419416, rs1793174, rs1883448, rs1905248, rs263247, rs3464′7183, rs35615951, rs3847233, rs3858038, rs4740708, rs528065, rs6459418, rs6577395, rs6811337, rs7680970, rs7684006, rs7698655, rs7961.005, rs8018807, rs9948620 or rs9953274,
one or more C alleles at the location of kgp10836214, kgp1432800, kgp22839559, kgp6301155, kgp6828277, rs2354380, rs2662, rs3858035, rs3894712, rs4797764 or rs7696391,
one or more G alleles at the location of kgp10148554, kgp10215554, kgp10989246, kgp11755256, kgp1682126, kgp1758575, kgp2920925, kgp3287349, kgp3420309, kgp3488270, kgp3598966, kgp3697615, kgp4137144, kgp5691690, kgp5924341, kgp5949515, kgp6213972, kgp625941, kgp6889327, kgp6990559, kgp7778345, kgp7932108, kgp8847137, kgp956070, rs1026894, rs11562998, rs11563025, rs11947777, rs12233980, rs12472695, rs13386874, rs1357718, rs1393037, rs1397481, rs1508515, rs16846161, rs209568, rs2618065, rs28993969, rs3768769, rs3858034, rs3858036, rs4978567, rs71.19480, rs7123506, rs7231366, rs7819949, rs7846783, rs7949751, rs8000689, rs961090 or rs967616, or
one or more T alleles at the location of rs12043743.
In some embodiments, the genotype of the subject at the location corresponding to the location of one or more of the SNPs is determined indirectly by determining the genotype of the subject at a location corresponding to the location of at least one SNP that is in linkage disequilibrium with the one or more SNPs.
The present invention also provides a kit for identifying a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis as a predicted responder or as a predicted non-responder to glatiramer acetate, the kit comprising at least one probe specific for the location of a SNP selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
The present invention also provides a kit for identifying a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis as a predicted responder or as a predicted non-responder to glatiramer acetate, the kit comprising at least one pair of PCR primers designed to amplify a DNA segment which includes the location of a SNP selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
The present invention also provides a kit for identifying a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis as a predicted responder or as a predicted non-responder to glatiramer acetate, the kit comprising a reagent for performing a method selected from the group consisting of restriction fragment length polymorphism (RFLP) analysis, sequencing, single strand conformation polymorphism analysis (SSCP), chemical cleavage of mismatch (CCM), gene chip and denaturing high performance liquid chromatography (DHPLC) for determining the genotype of the subject at a location corresponding to the location of at least one SNP selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
The present invention also provides a kit for identifying a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis as a predicted responder or as a predicted non-responder to glatiramer acetate, the kit comprising reagents for TaqMan Open Array assay designed for determining the genotype of the subject at a location corresponding to the location of at least one SNP selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
The present invention also provides a kit for identifying a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis as a predicted responder or as a predicted non-responder to glatiramer acetate, the kit comprising
a) at least one probe specific for a location corresponding to the location of at least one SNP;
b) at least one pair of PCR primers designed to amplify a DNA segment which includes a location corresponding to the location of at least one SNP;
c) at least one pair of PCR primers designed to amplify a DNA segment which includes a location corresponding to the location of at least one SNP and at least one probe specific for a location corresponding to the location of at least one SNP;
d) a reagent for performing a method selected from the group consisting of restriction fragment length polymorphism (PFLP) analysis, sequencing, single strand conformation polymorphism analysis (SSCP), chemical cleavage of mismatch (CCM), gene chip and denaturing high performance liquid chromatography (DHPLC) for determining the identity of at least one SNP; or
e) reagents for TaqMan Open Array assay designed for determining the genotype at a location corresponding to the location of at least one SNP,
wherein the at least one SNP is selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
In some embodiments, the at least one SNP is in linkage disequilibrium with the one or more SNPs.
In some embodiments, the gene chip is a whole genome genotyping array.
In some embodiments, the kit comprises
(i) at least one pair of PCR primers designed to amplify a DNA segment which includes the location of a SNP selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458, and
(ii) at least one probe specific for the location of a SNP selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
In some embodiments, the kit further comprises means for applying the algorithm depicted in FIG. 11 or FIG. 13 to identify the subject as a predicted responder or as a predicted non-responder to glatiramer acetate.
In some embodiments, the kit further comprises
a) a probe specific for the location of a SNP rs3135391;
b) one pair of PCR primers designed to amplify a DNA segment which includes the location of a SNP rs3135391;
c) a pair of PCR primers designed to amplify a DNA segment which includes a location corresponding to the location of a SNP rs3135391 and a probe specific for a location corresponding to the location of a SNP rs3135391;
d) a reagent for performing a method selected from the group consisting of restriction fragment length polymorphism (RFLP) analysis, sequencing, single strand conformation polymorphism analysis (SSCP), chemical cleavage of mismatch (CCM), gene chip and denaturing high performance liquid chromatography (DHPLC) for determining the genotype of the subject at a location corresponding to the location of a SNP rs3135391; or
e) reagents for TaqMan Open Array assay designed for determining the genotype of the subject at a location corresponding to the location of a SNP rs3135391,
and means for applying the algorithm depicted in FIG. 8, FIG. 9 or FIG. 10 to identify the subject as a predicted responder or as a predicted non-responder to glatiramer acetate.
In some embodiments, the location of a SNP selected from the group consisting of rs3135391, rs1894408, kpg6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
In some embodiments, the location of a SNP selected from the group consisting of kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
In some embodiments, the kit further comprises means for applying the algorithm depicted in FIG. 12 or FIG. 14 to identify the subject as a predicted responder or as a predicted non-responder to glatiramer acetate.
In some embodiments, the kit further comprises instructions for use of the kit for identifying a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis as a predicted responder or as a predicted non-responder to glatiramer acetate.
In some embodiments, the genotype of the subject at the location corresponding to the location of one or more of the SNPs is determined by indirect genotyping.
In some embodiments, the genotype of the subject at the location corresponding to the location of one or more of the SNPs is determined indirectly by determining the genotype of the subject at a location corresponding to the location of at least one SNP that is in linkage disequilibrium with the one or more SNPs.
In some embodiments, determining the genotype of the subject at a location corresponding to the location of at least one SNP that is in linkage disequilibrium with the one or more SNPs allows identification of the genotype of the subject at the location corresponding to the location of the one or more SNPs with a probability of at least 85%.
In some embodiments, wherein determining the genotype of the subject at a location corresponding to the location of at least one SNP that is in linkage disequilibrium with the one or more SNPs allows identification of the genotype of the subject at the location corresponding to the location of the one or more SNPs with a probability of at least 90%.
In some embodiments, wherein determining the genotype of the subject at a location corresponding to the location of at least one SNP that is in linkage disequilibrium with the one or more SNPs allows identification of the genotype of the subject at the location corresponding to the location of the one or more SNPs with a probability of at least 99%.
The present invention also provides a probe for identifying the genotype of a location corresponding to the location of a SNP selected from the group consisting of rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
In some embodiments, the location of a SNP selected from the group consisting of kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
In some embodiments, the SNP is in linkage disequilibrium with the one or more SNPs.
In some embodiments, the location of the SNP is determined indirectly by determining the genotype at a location corresponding to the location of the SNP that is in linkage disequilibrium with the one or more SNPs.
The present invention also provides Glatiramer acetate or a pharmaceutical composition comprising glatiramer acetate for use in treating a human subject afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis which human subject is identified as a predicted responder to glatiramer acetate by:
a) determining a genotype of the subject at a location corresponding to the location of one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of: rs1894408, kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458, and
b) identifying the subject as a predicted responder to glatiramer acetate if the genotype of the subject contains
one or more A alleles at the location of kgp8110667, rs10162089, rs759458 and kgp6214351, or
one or more G alleles at the location of kgp24415534, kgp6599438, kgp7747883, kgp8817856, rs16886004 and rs1894408.
In some embodiments, determining a genotype of the subject at a location corresponding to the location of one or more single nucleotide polymorphisms (SNPs) selected from the group consisting of: kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
In some embodiments, the genotype of the subject at the location corresponding to the location of one or more of the SNPs is determined indirectly by determining the genotype of the subject at a location corresponding to the location of at least one SNP that is in linkage disequilibrium with the one or more SNPs.
In some embodiments, determining the genotype of the subject at a location corresponding to the location of at least one SNP that is in linkage disequilibrium with the one or more SNPs allows identification of the genotype of the subject at the location corresponding to the location of the one or more SNPs with a probability of at least 85%, 90%, or 99%.
The present invention also provides a method of determining the genotype of a human subject comprising identifying whether the genotype of a human subject contains
one or more A alleles at the location of kgp8110667, rs10162089, rs759458 and kgp6214351, or
one or more G alleles at the location of kgp24415534, kgp6599438, kgp7747883, kgp8817856, rs16886004 and rs1894408.
In some embodiments, identifying whether the genotype of a human subject contains
one or more A alleles at the location of kgp8110667, rs10162089, rs759458 and kgp6214351, or
one or more G alleles at the location of kgp24415534, kgp6599438, kgp7747883, kgp8817856, rs16886004 and rs1894408
is determined indirectly by determining the genotype of the subject at a location corresponding to the location of at least one SNP that is in linkage disequilibrium with the one or more SNPs.
In some embodiments, identifying the genotype of a human subject at the location of kgp7747883, kgp6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458.
In some embodiments, the SNP is in linkage disequilibrium with the one or more SNPs.
In some embodiments, the genotype of the human subject is determined indirectly by determining the genotype of the human subject at a location corresponding to the location of the SNP that is in linkage disequilibrium with the one or more SNPs.
All combinations of the various elements described herein are within the scope of the invention.
DEFINITIONS As used herein, a genetic marker refers to a DNA sequence that has a known location on a chromosome. Several non-limiting examples of classes of genetic markers include SNP (single nucleotide polymorphism), STR (short tandem repeat), and SFP (single feature polymorphism). VNTR (variable number tandem repeat), microsatellite polymorphism, insertions and deletions. The genetic markers associated with the invention are SNPs. As used herein a SNP or “single nucleotide polymorphism” refers to a specific site in the genome where there is a difference in DNA base between individuals. In some embodiments the SNP is located in a coding region of a gene. In other embodiments the SNP is located in a noncoding region of a gene. In still other embodiments the SNP is located in an intergenic region.
Several non-limiting examples of databases from which information on SNPs or genes that are associated with human disease can be retrieved include: NCBI resources, The SNP Consortium LTD, NCBI dbSNP database, International HapMap Project, 1000 Genomes Project, Glovar Variation Browser, SNPStats, PharmGKB, GEN-SniP, and SNPedia.
SNPs are identified herein using the rs identifier numbers in accordance with the NCBI dbSNP database, which is publically available at: ncbi.nlm.nih.goviprojects/SNP/ or using the kgp identifier numbers, which were created by Illumina. Genotype at the kgp SNPs can be obtained by using the Illumina genotyping arrays. In addition, SNPs can be identified by the specific location on the chromosome indicated for the specific SNP.
Additional information about identifying SNPs can be obtained from the NCBI database SNP FAQ archive located at ncbi.nlm.nih.gov/books/NBK3848/ or from literature available on the Illumina website located at illumina.com/applications/genotyping/literature.ilmn.
In some embodiments, SNPs in linkage disequilibrium with the SNPs associated with the invention are useful for obtaining similar results. As used herein, linkage disequilibrium refers to the non-random association of SNPs at one loci. Techniques for the measurement of linkage disequilibrium are known in the art. As two SNPs are in linkage disequilibrium if they are inherited together, the information they provide is correlated to a certain extent. SNPs in linkage disequilibrium with the SNPs included in the models can be obtained from databases such as HapMap or other related databases, from experimental setups run in laboratories or from computer-aided in-silico experiments. Determining the genotype of a subject at a position of SNP as specified herein, e.g. as specified by NCBI dbSNP rs identifier, may comprise “direct genotyping”, e.g. by determining the identity of the nucleotide of each allele at the locus of SNP, and/or “indirect genotyping”, defined herein as evaluating/determining the identity of an allele at one or more loci that are in linkage disequilibrium with the SNP in question, allowing one to infer the identity of the allele at the locus of SNP in question with a substantial degree of confidence. In some cases, indirect genotyping may comprise determining the identity of each allele at one or more loci that are in sufficiently high linkage disequilibrium with the SNP in question so as to allow one to infer the identity of each allele at the locus of SNP in question with a probability of at least 85%, at least 90% or at least 99% certainty. A genotype at a position of SNP (genotype “at a” SNP) may be represented by a single letter which corresponds to the identity of the nucleotide at the SNP, where A represents adenine, T represents thymine, C represents cytosine, and G represents guanine. The identity of two alleles at a single SNP may be represented by a two letter combination of A, T, C, and G, where the first letter of the two letter combination represents one allele and the second letter represents the second allele, and where A represents adenine, T represents thymine, C represents cytosine, and G represents guanine. Thus, a two allele genotype at a SNP can be represented as, for example, AA, AT, AG, AC, TT, TG, TC, GG, GC, or CC. It is understood that AT, AG, AC, TG, TC, and GC are equivalent to TA, GA, CA, GT, CT, and CG, respectively.
The SNPs of the invention can be used as predictive indicators of the response to GA in subjects afflicted with multiple sclerosis or a single clinical attack consistent with multiple sclerosis. Aspects of the invention relate to determining the presence of SNPs through obtaining a patient DNA sample and evaluating the patient sample for the presence of one or more SNPs, or for a certain set of SNPs. It should be appreciated that a patient DNA sample can be extracted, and a SNP can be detected in the sample, through any means known to one of ordinary skill in art. Some non-limiting examples of known techniques include detection via restriction fragment length polymorphism (RFLP) analysis, arrays including but not limited to planar microarrays or bead arrays, sequencing, single strand conformation polymorphism analysis (SSCP), chemical cleavage of mismatch (CCM), Polymerase chain reaction (PCR) and denaturing high performance liquid chromatography (DHPLC).
In some embodiments, the genotyping array is a whole genome genotyping array. In some embodiments, the Whole-genome genotyping arrays as defined here are arrays that contain hundreds of thousands to millions of genetic sequences (which may also be named “probes”). In some embodiments, Whole-genome genotyping arrays contain 500,000 probes or more. In some embodiments, Whole-genome genotyping arrays contain 1 million probes or more. In some embodiments, Whole-genome genotyping arrays contain 5 million probes or more.
In some embodiments, a SNP is detected through PCR amplification and sequencing of the DNA region comprising the SNP. In some embodiments SNPs are detected using arrays, exemplified by gene chip, including but not limited to DNA arrays or microarrays, DNA chips, and whole genome genotyping arrays, all of which may be for example planar arrays or bead arrays, or a TaqMan open Array. Arrays/Microarrays for detection of genetic polymorphisms, changes or mutations (in general, genetic variations) such as a SNP in a DNA sequence, may comprise a solid surface, typically glass, on which a high number of genetic sequences are deposited (the probes), complementary to the genetic variations to be studied. Using standard robotic printers to apply probes to the array a high density of individual probe features can be obtained, for example probe densities of 600 features per cm2 or more can be typically achieved. The positioning of probes on an array is precisely controlled by the printing device (robot, inkjet printer, photolithographic mask etc) and probes are aligned in a grid. The organization of probes on the array facilitates the subsequent identification of specific probe-target interactions. Additionally it is common, but not necessary, to divide the array features into smaller sectors, also grid-shaped, that are subsequently referred to as sub-arrays. Sub-arrays typically comprise 32 individual probe features although lower (e.g. 16) or higher (e.g. 64 or more) features can comprise each sub-array. In some arrays the probes are connected to beads instead of the solid support. Such arrays are called “bead arrays” or “bead CHIPs”
In some embodiments, detection of genetic variation such as the presence of a SNP involves hybridization to sequences which specifically recognize the normal and the mutant allele in a fragment of DNA derived from a test sample. Typically, the fragment has been amplified, e.g. by using the polymerase chain reaction (PCR), and labeled e.g. with a fluorescent molecule. A laser can be used to detect bound labeled fragments on the chip and thus an individual who is homozygous for the normal allele can be specifically distinguished from heterozygous individuals (in the case of autosomal dominant conditions then these individuals are referred to as carriers) or those who are homozygous for the mutant allele. In some embodiments, the amplification reaction and/or extension reaction is carried out on the microarray or bead itself. For differential hybridization based methods there are a number of methods for analyzing hybridization data for genotyping: Increase in hybridization level: The hybridization levels of probes complementary to the normal and mutant alleles are compared. Decrease in hybridization level: Differences in the sequence between a control sample and a test sample can be identified by a decrease in the hybridization level of the totally complementary oligonucleotides with a reference sequence. A loss approximating 100% is produced in mutant homozygous Individuals while there is only an approximately 50% loss in heterozygotes. In Microarrays for examining all the bases of a sequence of “n” nucleotides (“oligonucleotide”) of length in both strands, a minimum of “2n” oligonucleotides that overlap with the previous oligonucleotide in all the sequence except in the nucleotide are necessary. Typically the size of the oligonucleotides is about 25 nucleotides. However it should be appreciated that the oligonucleotide can be any length that is appropriate as would be understood by one of ordinary skill in the art. The increased number of oligonucleotides used to reconstruct the sequence reduces errors derived from fluctuation of the hybridization level.
However, the exact change in sequence cannot be identified with this method; in some embodiments this method is combined with sequencing to identify the mutation. Where amplification or extension is carried out on the microarray or bead itself, three methods are presented by way of example: In the Minisequencing strategy, a mutation specific primer is fixed on the slide and after an extension reaction with fluorescent dideoxynucleotides, the image of the Microarray is captured with a scanner. In the Primer extension strategy, two oligonucleotides are designed for detection of the wild type and mutant sequences respectively. The extension reaction is subsequently carried out with one fluorescently labeled nucleotide and the remaining nucleotides unlabelled. In either case the starting material can be either an RNA sample or a DNA product amplified by PCR. In the Tag arrays strategy, an extension reaction is carried out in solution with specific primers, which carry a determined 5′ sequence or “tag”. The use of Microarrays with oligonucleotides complementary to these sequences or “tags” allows the capture of the resultant products of the extension. Examples of this include the high density Microarray “Flex-flex” (Affymetrix).
In the Illumina 1M Dou BeadChip array (illumina.com/products/humanlm_duo_dna_analysis_beadchip_kits.ilmn), SNP genotypes are generated from fluorescent intensities using the manufacturer's default cluster settings.
In some aspects of the invention measurement of clinical variables comprises part of the prediction model predicting response to GA along with the genetic variables. Some non-limiting examples are age of the patient (in years), gender of patient, clinical manifestations, MRI parameter, country, ancestry, and years of exposure to treatment) “Clinical manifestations” include but are not limited to EDSS score such as baseline EDSS score, log of number of relapses in last 2 Years and relapse rate. “MRI parameters” include but are not limited to the volume and/or number of T1 enhancing lesions and/or T2 enhancing lesions; exemplified by baseline volume of T2 lesion, number of Gd-T1 lesions at baseline. In certain aspect of the invention, the clinical variables taken into account are as measured at the time of the decision about the treatment suitable for the patient, or measured at a time point determined by the physician, researcher or other professional involved in the decision.
The identification of a patient as a responder or as a non-responder to GA based on the presence of at least one SNP from tables 2-22 and 24-33, a set of SNPs from tables 2-22 and 24-33, or the combination of a SNP or a set of SNPs from tables 2-22 and 24-33 with one or more clinical variables described above, may be used for predicting response to GA.
Also within the scope of the invention are kits and instructions for their use. In some embodiments kits associated with the invention are kits for identifying one or more SNPs within a patient sample. In some embodiments a kit may contain primers for amplifying a specific genetic locus. In some embodiments, a kit may contain a probe for hybridizing to a specific SNP. The kit of the invention can include reagents for conducting each of the following assays including but not limited to restriction fragment length polymorphism (RFLP) analysis, arrays including but not limited to planar microarrays or bead arrays, sequencing, single strand conformation polymorphism analysis (SSCP), chemical cleavage of mismatch (CCM), and denaturing high performance liquid chromatography (DHPLC), PCR amplification and sequencing of the DNA region comprising the SNP. A kit of the invention can include a description of use of the contents of the kit for participation in any biological or chemical mechanism disclosed herein. A kit can include instructions for use of the kit components alone or in combination with other methods or compositions for assisting in screening or diagnosing a sample and/or determining whether a subject is a responder or a non-responder to GA.
Forms of Multiple Sclerosis: There are five distinct disease stages and/or types of MS:
-
- 1) benign multiple sclerosis;
- 2) relapsing-remitting multiple sclerosis (RRMS);
- 3) secondary progressive multiple sclerosis (SPMS);
- 4) progressive relapsing multiple sclerosis (PRMS); and
- 5) primary progressive multiple sclerosis (PPMS).
Benign multiple sclerosis is a retrospective diagnosis which is characterized by 1-2 exacerbations with complete recovery, no lasting disability and no disease progression for 10-15 years after the initial onset. Benign multiple sclerosis may, however, progress into other forms of multiple sclerosis.
Patients suffering from RRMS experience sporadic exacerbations or relapses, as well as periods of remission. Lesions and evidence of axonal loss may or may not be visible on MRI for patients with RRMS. SPMS may evolve from RRMS. Patients afflicted with SPMS have relapses, a diminishing degree of recovery during remissions, less frequent remissions and more pronounced neurological deficits than RRMS patients. Enlarged ventricles, which are markers for atrophy of the corpus cailosum, midline center and spinal cord, are visible on MRI of patients with SPMS.
PPMS is characterized by a steady progression of increasing neurological deficits without distinct attacks or remissions. Cerebral lesions, diffuse spinal cord damage and evidence of axonal loss are evident on the MRI of patients with PPMS. PPMS has periods of acute exacerbations while proceeding along a course of increasing neurological deEicits without remissions. Lesions are evident on MRI of patients suffering from PRMS.(28)
A clinically isolated syndrome (CIS) is a single monosymptomatic attack compatible with MS, such as optic neuritis, brain stem symptoms, and partial myelitis. Patients with CIS that experience a second clinical attack are generally considered to have clinically definite multiple sclerosis (CDMS). Over 80 percent of patients with a CIS and MRI lesions go on to develop MS, while approximately 20 percent have a self-limited process.(29, 30) Patients who experience a single clinical attack consistent with MS may have at least one lesion consistent with multiple sclerosis prior to the development of clinically definite multiple sclerosis.
Multiple sclerosis may present with optic neuritis, blurring of vision, diplopia, involuntary rapid eye movement, blindness, loss of balance, tremors, ataxia, vertigo, clumsiness of a limb, lack of co-ordination, weakness of one or more extremity, altered muscle tone, muscle stiffness, spasms, tingling, paraesthesia, burning sensations, muscle pains, facial pain, trigeminal neuralgia, stabbing sharp pains, burning tingling pain, slowing of speech, slurring of words, changes in rhythm of speech, dysphagia, fatigue, bladder problems (including urgency, frequency, incomplete emptying and incontinence), bowel problems (including constipation and loss of bowel control), impotence, diminished sexual arousal, loss of sensation, sensitivity to heat, loss of short term memory, loss of concentration, or loss of judgment or reasoning.
Relapsing Form of Multiple Sclerosis: The term relapsing MS includes:
-
- 1) patients with RRMS;
- 2) patients with SPMS and superimposed relapses; and
- 3) patients with CIS who show lesion dissemination on subsequent MRI scans according to McDonald's criteria.
As used herein, relapsing forms of multiple sclerosis include: Relapsing-remitting multiple sclerosis (RRMS), characterized by unpredictable acute episodes of neurological dysfunction (relapses), followed by variable recovery and periods of clinical stability;
Secondary Progressive MS (SPMS), wherein patients having RRMS develop sustained deterioration with or without relapses superimposed; and
Primary progressive-relapsing multiple sclerosis (PPRMS) or progressive-relapsing multiple sclerosis (PRMS), an uncommon form wherein patients developing a progressive deterioration from the beginning can also develop relapses later on.
Kurtzke Expanded Disability Status Scale (EDSS):
The Kurtzke Expanded Disability Status Scale (EDSS) is a method of quantifying disability in multiple sclerosis. The EDSS replaced the previous Disability Status Scales which used to bunch people with MS in the lower brackets. The EDSS quantifies disability in eight Functional Systems (FS) and allows neurologists to assign a Functional System Score (FSS) in each of these. The Functional Systems are: pyramidal, cerebellar, brainstem, sensory, bowel and bladder, visual & cerebral (according to mult-sclerosis.org/expandeddisabilitystatusscale).
Clinical Relapse: A clinical relapse, which may also be used herein as “relapse,” “confirmed relapse,” or “clinically defined relapse,” is defined as the appearance of one or more new neurological abnormalities or the reappearance of one or more previously observed neurological abnormalities.
This change in clinical state must last at least 48 hours and be immediately preceded by a relatively stable or improving neurological state of at least 30 days. This criterion is different from the clinical definition of exacerbation “at least 24 hours duration of symptoms,” (31) as detailed in the section “relapse evaluation.”
An event is counted as a relapse only when the subject's symptoms are accompanied by observed objective neurological changes, consistent with:
a) an increase of at least 0.5 in the EDSS score or one grade in the score of two or more of the seven FS (32); or,
b) two grades in the score of one of FS as compared to the previous evaluation.
The subject must not be undergoing any acute metabolic changes such as fever or other medical abnormality. A change in bowel/bladder function or in cognitive function must not be entirely responsible for the changes in EDSS or FS scores.
As used herein, a “multiple sclerosis drug” is a drug or an agent intended to treat clinically defined MS, CIS, any form of neurodegenerative or demyelinating diseases, or symptoms of any of the above mentioned diseases. “Multiple sclerosis drugs” may include but are not limited to antibodies, immunosuppressants, anti-inflammatory agents, immunomodulators, cytokines, cytotoxic agents and steroids and may include approved drugs, drugs in clinical trial, or alternative treatments, intended to treat clinically defined MS, CIS or any form of neurodegenerative or demyelinatlng diseases. “Multiple sclerosis drugs” include but are not limited to Interferon and its derivatives (including BETASERON®, AVONEX® and REBIF®), Mitoxantrone and Natalizumab. Agents approved or in-trial for the treatment of other autoimmune diseases, but used in a MS or CIS patient to treat MS or CIS are also defined as multiple sclerosis drugs.
As used herein, a “naïve patient” is a subject that has not been treated with any multiple sclerosis drugs as defined in the former paragraph.
The administration of glatiramer acetate may be oral, nasal, pulmonary, parenteral, intravenous, intra-articular, transdermal, intradermal, subcutaneous, topical, intramuscular, rectal, intrathecal, intraocular, buccal or by gavage.
As used herein, “GALA” is a phase 3 clinical trial entitled “A Study in Subjects With Relapsing-Remitting Multiple Sclerosis (RRMS) to Assess the Efficacy, Safety and Tolerability of Glatiramer Acetate (GA) Injection 40 mg Administered Three Times a Week Compared to Placebo (GALA).” The GALA trial has the ClinicalTrials.gov Identifier NCT01067521, and additional information about the trial can be found at clinicaltrials.gov/ct2/show/NCT01067521.
As used herein, “FORTE” is a phase 3 clinical trial entitled “Clinical Trial Comparing Treatment of Relapsing-Remitting Multiple Sclerosis (RR-MS) With Two Doses of Glatiramer Acetate (GA).” The FORTE trial has the ClinicalTrials.gov Identifier NCT00337779 and additional information, including study results can be found at clinicaltrials.gov/ct2/show/NCT00337779.
As used herein, “about” with regard to a stated number encompasses a range of +10 percent to −10 percent of the stated value. By way of example, about 100 mg/kg therefore includes the range 90-100 mg/kg and therefore also includes 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 018, 109 and 110 mg/kg. Accordingly, about 100 mg/kg includes, in an embodiment, 100 mg/kg.
It is understood that where a parameter range is provided, all integers within that range, tenths thereof, and hundredths thereof, are also provided by the invention. For example, “0.2-5 mg/kg” is a disclosure of 0.2 mg/kg, 0.21 mg/kg, 0.22 mg/kg, 0.23 mg/kg etc. up to 0.3 mg/kg, 0.31 mg/kg, 0.32 mg/kg, 0.33 mg/kg etc. up to 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg etc. up to 5.0 mg/kg.
All combinations of the various elements described herein are within the scope of the invention.
This invention will be better understood by reference to the Experimental Details which follow, but those skilled in the art will readily appreciate that the specific experiments detailed are only illustrative of the invention as described more fully in the claims which follow thereafter.
Experimental Details Description of the Study Copaxone® (Glatiramer acetate) is a leading drug for the treatment of MS that is marketed by TEVA. Glatiramer acetate significantly improves patient outcomes, but glatiramer acetate treatment is not equally effective in all patients. Individual differences between patients, including inherited genetic factors, can account for significant differences in individual responses to medications. A consequence of this diversity is that no single medication is effective in all patients. Clinical and genetic factors are predictive of patient response to glatiramer acetate.
In the following Examples, predictive genetic factors of glatiramer acetate treatment response are identified and a diagnostic model is demonstrated to help guide MS drug therapy to significantly improve patient outcomes.
EXAMPLES Example 1 Patient Populations Response definitions were received from patients from two large glatiramer acetate clinical trial cohorts (GALA, FORTE) and patients were categorized as responder, non-responder, extreme-responder, or extreme non-responder according to the criteria set forth in Table 1.
TABLE 1
Definition of Glatiramer Acetate Responders and Non-Responders
and population representation in GALA and FORTE cohorts.
Number of samples
(% of cohort)
GALA
GALA FORTE placebo
Responders Responders: 200 221 97
Change in Annual Relapse (26%) (36%) (25%)
Rate (ARR) from previous
2 years < −1
Extreme Responders: 66 95 23
Change in ARR from previous (8.5%) (16%) (6%)
2 years < −1 and new T2
Lesions = 0 and Relapse
Free
Non- Non-Responders: 123 68 101
Responders Change in ARR from previous (16%) (11%) (26%)
2 years ≧ 0
Extreme Non-Responders: 79 38 73
Change in ARR from previous (10%) (6%) (19%)
2 years ≧ 0 and new T2
Lesions ≧ 1
Example 2 Patient Genotyping DNA samples from categorized patients were subject to quality control analysis followed by genotyping with the Illumina OMNI-5M genome wide array. This array tests 4,301,331 variants with a median marker spacing of 360 bp. The array includes 84,004 non-synonymous SNPs including 43,904 variants in the MHC region. Over 800 patients were genotyped.
Genotyping Quality Control An Illumina-derived algorithm of SNP cluster definitions (i.e., the specific parameters used to determine specific genotypes of each SNP) was used to determine the 4,301,331 genotypes for each of the genotyped samples. For genotyping QC, SNPs were evaluated as either pass, fail, or the SNP cluster calling definitions were revised and the SNP was re-evaluated as pass or fail.
Evaluation of SNPs with poor cluster separation values (i.e., the location of SNP calling clusters were very close together) identified 126 SNPs for which SNP clustering was manually corrected. Evaluation of SNPs that were not in Hardy-Weinburg equilibrium identified 1,000 SNPs for which SNP clustering was manually corrected. Evaluation of SNPs with low GC scores (GC score: an Illumina-developed score of overall SNP performance) identified 10,000 SNPs for which SNP clustering was manually corrected. Evaluation of SNPs with low GC scores also identified 160,000 SNPs for which SNP clustering was revised using Illumina GenomeStudio software to re-define SNP cluster calling definitions. A total of 524 SNPs were scored as “failed” and removed from further analyses due to poor SNP clustering that could not be manually corrected.
In addition, SNPs with low call rates (i.e., a low number of genotype calls were generated from a particular SNP test) were scored as “fail” and removed from further analyses. Applying a “call rate” threshold of >85% to the 4,301,331 SNPs tested (i.e., for each SNP, the % of samples for which a genotype was called) resulted in “fails” for 4,384 SNPs, yielding a total of 4,296,423 SNPs available for subsequent analyses (99.89% of variants tested).
Finally, samples with call rates less than 94% (i.e., samples for which less than 94% of the genotyped SNPs produced genotype calls) were removed. This resulted in the removal of 31 samples with call rates of 49-93%, and resulted in a final cohort of 776 samples for subsequent analyses. Notably, of these 31 excluded samples, 18 (58%) had very low (<1 ng/ul) DNA concentrations and 12 of the other 13 excluded samples had low DNA quality (OD 260/280 ratio <1.8 or >2.0), or low DNA volumes.
For the final 776 samples, the overall median sample genotype call rate was 99.88% (min. 94.26%, max. 99.96%) indicative of high quality genotype data for these samples.
Example 3 Overview of Genetic Analysis Genotype data was merged with selected clinical data (Responder/Non-Responder status, country, age, gender, ancestry, log of number of relapses in last 2 Years, baseline EDSS score, baseline volume of T2 lesion, number of Gd-T1 lesions at baseline, and years of exposure to treatment). Association and regression analyses were conducted using SVS7 software.
Analyses were conducted using standard association analyses and regression analyses. To maximize the statistical power for high priority variants, the analyses began with focused list of candidate variants (35), then expanded to a larger number of variants in 30 genes, then expanded to variants in 180 candidate genes, and finally expanded to the entire genome-wide analysis.
For each stage of association analyses, results were calculated to identify genetic associations using three genetic models:
1. Allelic Model (chi-square, chi-square −10 Log P, fisher exact, fisher exact −10 Log P, values for fisher and chi-square with Bonferoni correction, Odds Ratios and Confidence Bounds, Begression P-value, Regression −log 10 P, Call Rate (Cases), Call Rate (Controls), Minor Allele Frequency, Allele Freq. (Cases), Allele Freq. (Controls), Major Allele Frequency, Allele Freq. (Cases), Allele Freq. (Controls), Genotype Counts for cases and controls, Missing Genotype Counts, Allele Counts for cases and controls).
2. Additive Model (Cochrane-Armitage Trend Test P-value, Exact for of Cochrane Armitage Trend Test, −log 10 P-values, Correlation/Trend test P-value, Correlation/Trend −log 10 P, Call Rate, Call Rate (Cases), Call Rate (Controls), Minor Allele Frequency, Allele Freq. (Cases), Allele Freq. (Controls).
For each stage of regression analyses, results were calculated to identify genetic associations using an additive genetic model.
Example 4 Stages of Analysis Stage 1.
Discovery Cohort (n=318: 198 R vs. 120 NR)—In the first stage of analysis, the discovery cohort (GALA) was analyzed to identify variants associated with good response vs. poor response.
Stage 2.
Replication Cohort (n=262: 201 R vs. 61 NR)—In the second stage of each analysis, variants selected in the discovery cohort were analyzed to identify replicating associations in the FORTE replication cohort associated with good response vs. poor response.
Stage 3.
Combined Cohorts (n=580: 399 R vs. 111 NR)—In the third stage of the analysis, the combined GALA and FORTE cohorts were analyzed.
Stage 4. Placebo Cohort (n=196: 95 R vs. 101 NR) In the fourth stage of the analysis, the placebo cohort (GALA placebo) was analyzed to identify variants associated with placebo response/non-response. These results will be used to confirm whether significantly associated variants are specific to glatiramer acetate drug response versus disease severity.
An overview of these analyses is presented in Table A. For each stage a step-wise analysis was performed in order to maximize study power.
TABLE A
Overview of the analyses used to identify genetic markers
predictive of response to glatiramer acetate.
Combined Cohorts for
Discovery Cohort Replication Cohort Comparative Parameters
Step 1 Candidate SNPs (35) Candidate SNPs (35) Candidate SNPs (35)
−Additive, Allelic, −Additive, Allelic, −Additive, Allelic,
Genotypic, Regression Genotypic, Regression Genotypic, Regression
Candidate SNPs. Extreme Candidate SNPs, Extreme Candidate SNPs, Extreme
−Additive, Allelic, −Additive, Allelic, −Additive, Allelic,
Genotypic, Regression Genotypic, Regression Genotypic, Regression
Step 2 Candidate Genes (30) Candidate Genes (30) Candidate Genes (30)
−Additive, Allelic, −Additive, Allelic, −Additive, Allelic,
Genotypic, Regression Genotypic, Regression Genotypic, Regression
Candidate Genes, Extreme Candidate Genes, Extreme Candidate Genes, Extreme
−Additive, Allelic, −Additive, Allelic, −Additive, Allelic,
Genotypic, Regression Genotypic, Regression Genotypic, Regression
Step 3 Candidate Genes (180) Candidate Genes (180) Candidate Genes (180)
−Additive, Allelic, −Additive, Allelic, −Additive, Allelic,
Genotypic, Regression Genotypic, Regression Genotypic, Regression
Candidate Genes, Extreme Candidate Genes, Extreme Candidate Genes, Extreme
−Additive, Allelic, −Additive, Allelic, −Additive, Allelic,
Genotypic, Regression Genotypic, Regression Genotypic, Regression
Step 4 Genome-wide Genome-wide Genome-wide
−Additive, Allelic, −Additive, Allelic, −Additive, Allelic,
Genotypic, Regression Genotypic, Regression Genotypic, Regression
+Corrected for ancestry +Corrected for ancestry +Corrected for ancestry
+Corrected for +Corrected for +Corrected for
clinical covariates clinical covariates clinical covariates
+Corrected for top SNP +Corrected for top SNP +Corrected for top SNP
Genome-wide, Extreme Genome-wide, Extreme Genome-wide, Extreme
−Additive, Allelic, −Additive, Allelic, −Additive, Allelic,
Genotypic, Regression Genotypic, Regression Genotypic, Regression
+Corrected for +Corrected for +Corrected for
clinical covariates clinical covariates clinical covariates
+Corrected for top SNP +Corrected for top SNP +Corrected for top SNP
Example 5 Analysis Part 1—Analysis of Candidate Variants The initial analysis was limited to 35 genetic variants identified in high priority genes. Power (80%) with Bonferroni statistical correction for multiple testing to identify significant gernetic associations with an odds ratio >3, for variants with an allele frequency greater than 10%. (Or rare alleles (2.5%) with an odds ratio >7).
Results for Standard Response Definition, Candidate Variants Selected a priori for Additive and Allelic models are presented in tables 2 and 3, respectively.
TABLE 2
Additive Model, Candidate Variants (GALA, FORTE, and Combined cohorts)
GALA FORTE COMBINED
Al- Al- Al-
Armi- Al- lele Armi- Al- lele Armi- Al- lele
tage lele Freq. tage lele Freq. tage lele Freq.
P- Odds Freq. (Non- P- Odds Freq. (Non- P- Odds Freq. (Non- Muta-
Source Name Ch Gene value Ratio (Resp.) Resp.) value Ratio (Resp.) Resp.) value Ratio (Resp.) Resp.) tion
Top Priority Tchelet GWAS rs3135391 6 HLA-DRB1 0.040 0.66 17% 24% 0.0499 0.64 23% 32% 0.014 0.70 20% 27% *1501, T118T
Top Priority Tchelet GWAS rs3135388 6 HLA-DRB1 0.047 0.67 17% 24% 0.0499 0.64 23% 32% 0.017 0.70 20% 27% *1501
Tchelet GWAS rs947603 10 CEP55 0.054 1.48 26% 19% 0.16 1.45 23% 16% 0.027 1.42 24% 18%
Top Priority Tsareva 2011 rs1800629 6 TNF 0.088 0.68 12% 17% 0.65 0.88 12% 14% 0.09 0.75 12% 16%
Tchelet GWAS rs4344916 2 AC083939.1 0.32 1.20 34% 30% 0.48 0.87 34% 38% 0.70 1.05 34% 33%
Tchelet GWAS rs10950359 7 AC074389.1 0.32 0.85 29% 33% 0.40 1.23 25% 21% 0.51 0.91 27% 29%
Tchelet GWAS rs12256889 10 CYP26C1 0.33 0.84 31% 35% 0.064 1.56 33% 25% 0.77 1.04 32% 31%
Top Priority Comi rs974060 7 TAC1 0.34 1.18 32% 28% 0.78 0.94 27% 29% 0.67 1.06 30% 28%
Top Priority Tchelet GWAS rs17771939 8 AC016885.1 0.36 1.18 29% 26% 0.0032 0.54 28% 43% 0.35 0.88 29% 31%
Top Priority Tsareva 2011 rs6897932 5 IL7Ra 0.39 0.84 20% 23% 0.63 0.90 24% 26% 0.44 0.89 22% 24% Missense T244I
Tchelet GWAS rs11599624 10 P11-655H13 0.39 1.23 15% 13% 0.50 1.27 11% 9% 0.43 1.17 13% 12%
Top Priority Comi rs1558896 7 TAC1 0.40 1.15 34% 30% 0.85 0.96 29% 30% 0.73 1.05 31% 30%
Tchelet GWAS rs11617134 13 P11-629E24 0.41 0.76 5% 7% 0.95 1.02 7% 7% 0.64 0.89 6% 7%
Tchelet GWAS rs17575455 2 AC078940.2 0.41 0.87 33% 36% 0.0062 0.56 31% 44% 0.019 0.73 32% 39%
Top Priority Grossman 2007 rs946685 1 IL12RB2 0.43 1.19 17% 15% 0.22 1.47 18% 13% 0.17 1.28 18% 14%
Tchelet GWAS rs4343256 15 CRTC3 0.47 1.27 8% 6% 0.71 0.86 7% 8% 0.72 1.09 8% 7%
Tchelet GWAS rs6097801 20 CYP24A1 0.47 0.84 11% 13% 0.27 0.75 14% 18% 0.29 0.83 13% 15%
Tchelet GWAS rs1007328 15 AC012409.1 0.50 0.89 48% 51% 0.050 0.66 47% 57% 0.08 0.80 48% 53%
Top Priority Tsareva 2011 rs231775 2 CTLA4 0.51 1.12 42% 39% 0.59 1.11 40% 37% 0.46 1.10 41% 38% Missense T17A
Top Priority Tchelet GWAS rs9944913 18 NOL4 0.52 0.84 10% 12% 0.054 0.55 9% 15% 0.08 0.71 9% 13%
Tchelet GWAS rs1573706 20 PTPRT 0.55 0.88 17% 19% 0.15 0.69 17% 22% 0.19 0.80 17% 20%
Top Priority Grossman 2007 rs1415148 1 CTSS 0.56 0.90 39% 41% 0.38 1.20 41% 36% 0.88 1.02 40% 39%
Tchelet GWAS rs2487896 10 HPSE2 0.57 0.88 14% 16% 0.0006 0.39 12% 25% 0.013 0.65 13% 19%
Tchelet GWAS rs10931091 2 AC074182.1 0.58 1.17 11% 9% 0.53 0.80 7% 9% 0.88 0.97 9% 9%
Top Priority Comi rs269976 18 SLC14A2 0.59 1.18 8% 7% 0.22 1.75 8% 5% 0.26 1.32 8% 6%
Top Priority Grossman 2007 rs2275235 1 CTSS 0.62 0.91 34% 35% 0.25 1.28 37% 31% 0.66 1.06 35% 34%
Tchelet GWAS rs4369324 10 P11-655H13 0.64 1.10 25% 23% 0.25 1.37 20% 15% 0.49 1.11 22% 20%
Top Priority Tchelet GWAS rs4148871 6 TAP2 0.69 0.93 21% 22% 0.37 1.27 23% 19% 0.79 1.04 22% 21%
Grossman 2007 rs2001791 3 CD86 0.74 1.08 14% 13% 0.036 0.58 13% 21% 0.36 0.85 14% 16%
Tchelet GWAS rs10988087 9 SET 0.77 0.89 4% 4% 0.0062 0.38 4% 11% 0.065 0.61 4% 7%
Grossman 2007 rs1129055 3 CD86 0.83 1.04 26% 25% 0.40 0.84 30% 34% 0.97 0.99 28% 28% Missense A228
Tchelet GWAS rs10853605 18 MEX3C 0.91 1.02 43% 43% 0.34 1.22 44% 39% 0.49 1.09 44% 41%
Top Priority Comi rs4890535 18 SLC14A2 0.94 1.02 9% 9% 0.48 1.31 9% 7% 0.66 1.10 9% 9%
Tchelet GWAS rs2177073 18 DTNA 0.95 1.02 11% 11% 0.033 0.55 10% 17% 0.21 0.79 11% 13%
Top Priority Tchelet GWAS rs2521644 7 NPY 0.97 0.99 43% 43% 0.64 1.10 47% 44% 0.67 1.06 45% 44%
indicates data missing or illegible when filed
TABLE 3
Allelic Model, Candidate Variants (GALA, FORTE, and Combined cohorts)
GALA FORTE COMBINED
Odds Al- Odds Al- Odds Al-
Ratio Al- lele Ratio Al- lele Ratio Al- lele
Fisher's (Minor lele Freq. Fisher's (Minor lele Freq. Fisher's (Minor lele Freq.
Exact Al- Freq. (Non- Exact Al- Freq. (Non- Exact Al- Freq. (Non- DD Dd dd DD Dd dd
Name Ch. Gene(s) P lele) (Resp.) Resp.) P lele) (Resp.) Resp.) P lele) (Resp.) Resp.) (Cases) (Cases) (Cases) (Cntls) (Cntls) (Cntls)
rs3135391 6 HLA-DRB1 0.041 0.66 0.17 0.24 0.057 0.64 0.23 0.32 0.015 0.70 0.20 0.27 20 122 257 10 77 94
rs3135388 6 HLA-DRB1 0.051 0.67 0.17 0.24 0.057 0.64 0.23 0.32 0.018 0.70 0.20 0.27 20 122 257 10 76 94
rs947603 10 CEP55 0.066 1.46 0.26 0.19 0.16 1.48 0.23 0.16 0.027 1.43 0.24 0.18 22 148 228 8 50 123
rs1800629 6 TNF 0.10 0.67 0.12 0.17 0.64 0.86 0.12 0.14 0.09 0.73 0.12 0.16 10 77 310 6 46 129
rs10950359 7 AC074389.1 0.33 0.83 0.29 0.33 0.47 1.24 0.25 0.21 0.52 0.91 0.27 0.29 39 138 222 14 77 90
rs974060 7 TAC1 0.33 1.19 0.32 0.28 0.82 0.94 0.27 0.29 0.68 1.06 0.30 0.28 46 145 208 11 81 89
rs12256889 10 CYP26C1 0.34 0.84 0.31 0.35 0.07 1.53 0.33 0.25 0.79 1.04 0.32 0.31 39 178 182 19 75 87
rs17771939 8 AC016885.1 0.36 1.19 0.29 0.26 0.004 0.53 0.28 0.43 0.33 0.88 0.29 0.31 35 159 205 22 70 89
rs4344916 2 AC083939.1 0.38 1.18 0.34 0.30 0.45 0.85 0.34 0.38 0.74 1.05 0.34 0.33 52 167 179 18 83 80
rs11599624 10 RP11-655H13.1 0.42 1.23 0.15 0.13 0.62 1.27 0.11 0.09 0.45 1.17 0.13 0.12 7 92 300 3 36 142
rs6897932 5 IL7Ra 0.43 0.84 0.20 0.23 0.63 0.89 0.24 0.26 0.45 0.89 0.22 0.24 21 135 242 13 62 106
rs1558896 7 TAC1 0.43 1.17 0.34 0.30 0.91 0.96 0.29 0.30 0.73 1.05 0.31 0.30 53 142 203 11 87 83
rs17575455 2 AC078940.2 0.44 0.87 0.33 0.36 0.006 0.56 0.31 0.44 0.023 0.73 0.32 0.39 42 170 186 26 89 66
rs946685 1 IL12RB2 0.44 1.20 0.17 0.15 0.27 1.41 0.18 0.13 0.20 1.27 0.18 0.14 10 119 268 2 48 131
rs6097801 20 CYP24A1 0.46 0.83 0.11 0.13 0.24 0.72 0.14 0.18 0.26 0.82 0.13 0.15 14 72 313 3 48 130
rs11617134 13 RP11-629E24.2 0.48 0.74 0.05 0.07 1.00 1.03 0.07 0.07 0.69 0.88 0.06 0.07 3 41 355 1 22 158
rs1007328 15 AC012409.1 0.51 0.90 0.48 0.51 0.063 0.67 0.47 0.57 0.10 0.80 0.48 0.53 88 204 107 48 96 37
rs4343256 15 CRTC3 0.53 1.26 0.08 0.06 0.70 0.87 0.07 0.08 0.81 1.09 0.08 0.07 1 58 340 0 25 155
rs231775 2 CTLA4 0.56 1.11 0.42 0.39 0.60 1.13 0.40 0.37 0.48 1.10 0.41 0.38 68 189 142 28 83 70
rs2487896 10 HPSE2 0.56 0.88 0.14 0.16 0.001 0.43 0.12 0.25 0.016 0.66 0.13 0.19 6 92 301 6 55 119
rs1573706 20 PTPRT 0.59 0.88 0.17 0.19 0.18 0.70 0.17 0.22 0.21 0.81 0.17 0.20 7 120 272 7 58 116
rs9944913 18 NOL4 0.60 0.85 0.10 0.12 0.060 0.55 0.09 0.15 0.10 0.71 0.09 0.13 2 71 326 3 40 138
rs1415148 1 CTSS 0.62 0.91 0.39 0.41 0.40 1.22 0.41 0.36 0.90 1.02 0.40 0.39 60 195 142 27 88 66
rs269976 18 SLC14A2 0.65 1.19 0.08 0.07 0.32 1.73 0.08 0.05 0.29 1.33 0.08 0.06 3 60 336 2 19 160
rs2275235 1 CTSS 0.67 0.92 0.34 0.35 0.28 1.30 0.37 0.31 0.69 1.06 0.35 0.34 47 187 164 19 85 77
rs10931091 2 AC074182.1 0.68 1.16 0.11 0.09 0.56 0.78 0.07 0.09 0.91 0.97 0.09 0.09 3 65 331 3 27 150
rs4148871 6 TAP2 0.69 0.92 0.21 0.22 0.45 1.26 0.23 0.19 0.82 1.04 0.22 0.21 18 137 244 10 56 115
rs4369324 10 RP11-655H13.2 0.70 1.10 0.25 0.23 0.29 1.41 0.20 0.15 0.49 1.12 0.22 0.20 23 132 244 9 56 116
rs2001791 3 CD86 0.81 1.09 0.14 0.13 0.044 0.57 0.13 0.21 0.37 0.85 0.14 0.16 11 87 301 5 47 129
rs10988087 9 SET 0.83 0.89 0.04 0.04 0.008 0.36 0.04 0.11 0.08 0.60 0.04 0.07 1 31 367 1 22 156
rs10853605 18 MEX3C 0.93 1.02 0.43 0.43 0.35 1.23 0.44 0.39 0.52 1.09 0.44 0.41 79 190 130 27 96 58
rs2521644 7 NPY 1.00 0.99 0.43 0.43 0.68 1.11 0.47 0.44 0.70 1.06 0.45 0.44 83 193 123 33 92 56
rs2177073 18 DTNA 1.00 1.02 0.11 0.11 0.036 0.53 0.10 0.17 0.23 0.78 0.11 0.13 4 77 317 5 38 138
rs4890535 18 SLC14A2 1.00 1.02 0.09 0.09 0.59 1.31 0.09 0.07 0.74 1.11 0.09 0.09 5 65 329 4 23 154
rs1129055 3 CD86 1.00 1.00 0.25 0.26 1.00 1.00 0.31 0.30 1.00 1.00 0.28 0.28 45 236 299 33 158 208
In some embodiments genetic markers presented in Tables 2 and 3 are identified as predictive of response to glatiramer acetate if the p-value for the GALA cohort is less than about 0.12, less than about 0.08, less than about 0.05, less than about 0.01 or less than about 0.005.
In some embodiments genetic markers presented in Tables 2 and 3 are identified as predictive of response to glatiramer acetate if the p-value for the FORTE cohort is less than about 0.12, less than about 0.08, less than about 0.05, less than about 0.01, less than about 0.005 or less than about 0.001.
In some embodiments genetic markers presented in Tables 2 and 3 are identified as predictive of response to glatiramer acetate if the p-value for the Combined cohort is less than about 0.12, less than about 0.08, less than about 0.05, less than about 0.01, less than about 0.005 or less than about 0.001.
Example 6 Analysis Part 2—Analysis of Candidate Genes (30) The second analysis was limited to a selected set of genetic variants in 30 priority candidate genes (4,012 variants). Power (80%) to identify significant genetic associations with an odds ratio >4, for variants with an allele frequency greater than 10%. (Or rare alleles (5%) with an odds ratio >6).
Results for Standard Response Definition, Top 30 Candidate Genes Selected a priori for Additive and Allelic models are presented in tables 4-5, respectively.
In some embodiments genetic markers presented in Tables 4-5 are identified as predictive of response to glatiramer acetate if the p-value for the GALA cohort is less than about 0.05, less than about 0.01 or less than about 0.005.
In some embodiments genetic markers presented in Tables 4-5 are identified as predictive of response to glatiramer acetate if the p-value for the FORTE cohort is less than about 0.10, less than about 0.05, less than about 0.01, less than about 0.005 or less than about 0.001.
TABLE 4
Additive Model, Analysis of Candidate Genes (30) (GALA, FORTE, and Combined cohorts)
GALA FORTE
Al- Al- COMBINED
Armi- Al- lele Armi- Al- lele Al-
tage lele Freq. tage lele Freq. Armi- lele
P- Odds Freq. (Non- P- Odds Freq. (Non- tage Odds Freq.
Name Ch Gene value Ratio (Resp.) Resp.) value Ratio (Resp.) Resp.) P-value Ratio (Resp.)
rs1894407 6 HLA-DOB/TAP2 0.002 1.77 42% 30% 0.02 1.72 40% 29% 0.00011 1.73 41%
rs1894406 6 HLA-DOB/TAP2 0.003 1.74 40% 29% 0.02 1.76 36% 25% 0.00027 1.68 38%
kgp11795987 6 ? 0.003 2.04 20% 11% 0.22 1.46 16% 11% 0.00276 1.75 18%
rs1894408 6 HLA-DOB/TAP2 0.003 1.72 42% 31% 0.01 1.82 41% 28% 0.00010 1.73 41%
kgp9296959 10 ? 0.004 0.20 1% 5% 0.20 2.59 4% 2% 0.30615 0.69 3%
kgp12268594 3 ? 0.004 0.23 1% 5% 0.4 0.59 2% 3% 0.00427 0.35 2%
kgp26488438 6 TAP1 0.004 0.23 1% 5% 0.57 1.85 1% 1% 0.01316 0.37 1%
kgp8900813 6 ? 0.004 1.96 20% 11% 0.23 1.44 16% 11% 0.00456 1.69 18%
kgp6474885 6 TNF 0.004 1.96 20% 11% 0.26 1.41 16% 12% 0.00506 1.68 18%
rs909253 6 TAP2 0.004 0.61 25% 36% 0.81 0.94 27% 28% 0.01033 0.70 26%
kgp5854183 18 NOL4, NOL4, 0.005 0.14 1% 3% 0.65 1.34 3% 2% 0.21372 0.61 2%
NOL4, NOL4,
NOL4
kgp9319993 3 CCR5, CCR5 0.005 1.60 48% 37% 0.76 1.06 45% 43% 0.01738 1.36 47%
rs2857103 6 TAP2 0.006 1.70 37% 27% 0.00 2.04 36% 22% 0.00011 1.78 36%
kgp10224254 6 HLA-DOB 0.006 1.63 42% 32% 0.04 1.58 39% 29% 0.00115 1.56 40%
kgp418674 6 LTA, LTA 0.006 0.62 25% 36% 0.78 0.94 27% 28% 0.01249 0.71 26%
rs241451 6 TAP2 0.006 1.69 37% 27% 0.01 1.86 35% 23% 0.00026 1.72 36%
kgp6137749 3 CCR5, CCR5 0.006 1.58 48% 37% 0.85 1.04 45% 44% 0.02225 1.34 47%
rs9501224 6 TAP2 0.007 1.69 37% 27% 0.00 2.04 36% 22% 0.00013 1.77 36%
kgp9296977 3 ? 0.007 1.61 37% 26% 0.49 1.16 35% 31% 0.00963 1.42 36%
rs2071469 6 HLA-DOB 0.007 1.62 43% 32% 0.04 1.58 39% 29% 0.00140 1.55 41%
kgp10991488 3 CCR5, CCR5 0.007 1.57 48% 37% 0.75 1.07 45% 43% 0.02091 1.35 47%
kgp12106435 18 MBP, MBP 0.007 0.52 9% 16% 0.08 0.57 7% 12% 0.00055 0.52 8%
kgp9394249 18 MBP, MBP 0.009 ~Infinity 3% 0% 0.78 0.84 2% 2% 0.08317 2.77 2%
kgp4490237 6 ? 0.009 0.28 2% 5% 0.57 1.85 1% 1% 0.02180 0.40 2%
kgp3275166 18 SLC14A2 0.010 ? 0% 2% 0.86 1.22 1% 1% 0.11305 0.36 1%
kgp7178883 18 SLC14A2 0.010 0.27 1% 5% 0.26 3.12 3% 1% 0.11795 0.56 2%
rs241443 6 TAP2 0.011 1.63 37% 27% 0.01 2.01 35% 22% 0.00030 1.71 36%
kgp5249257 3 CCR5, CCR5 0.011 1.56 37% 27% 0.37 1.22 35% 30% 0.00992 1.42 36%
kgp721209 3 CCR5, CCR5 0.011 1.56 37% 27% 0.37 1.22 35% 30% 0.00992 1.42 36%
kgp4209856 3 ? 0.011 1.56 37% 27% 1.57 1.14 35% 32% 0.01636 1.39 36%
kgp10626023 18 NOL4, NOL4, 0.011 1.72 24% 15% 0.70 1.11 20% 18% 0.03243 1.42 22%
NOL4, NOL4,
NOL4, NOL4
kgp5162959 3 CCR5, CCR5 0.011 1.55 37% 27% 0.34 1.23 35% 30% 0.00913 1.42 36%
kgp2033254 6 PSMB9 0.012 0.17 1% 3% 0.68 0.60 0% 1% 0.00750 0.22 1%
kgp3509792 18 NOL4, NOL4, 0.013 0.42 3% 8% 0.10 3.26 5% 2% 0.21865 0.71 4%
NOL4, NOL4,
NOL4
Additive Model, Analysis of Candidate Genes (30) (GALA, FORTE, and Combined cohorts)
COMBINED
Al-
lele
Freq. DD Dd dd D d
(Non- DD (Con- Dd (Con- dd (Con- D (Con- d (Con-
Name Resp.) (Cases) trols) Cases) trols) (Cases) trols) (Cases) trols) (Cases) trols)
rs1894407 30% 57 16 213 75 128 90 327 107 469 255
rs1894406 27% 51 13 202 73 146 95 304 99 494 263
kgp11795987 11% 16 3 111 33 271 144 143 39 653 321
rs1894408 30% 58 16 211 74 127 89 327 106 465 252
kgp9296959 4% 0 0 20 13 376 168 20 13 772 349
kgp12268594 4% 0 0 13 16 386 165 13 16 785 346
kgp26488438 4% 0 0 11 13 388 168 11 13 787 349
kgp8900813 11% 16 3 112 35 270 143 144 41 652 321
kgp6474885 11% 16 3 112 35 270 142 144 41 652 319
rs909253 33% 30 19 146 83 220 79 206 121 586 241
kgp5854183 3% 0 0 15 11 383 170 15 11 781 351
kgp9319993 39% 84 30 203 82 110 69 371 142 423 220
rs2857103 25% 39 11 211 69 149 100 289 91 509 269
kgp10224254 31% 59 18 205 75 135 88 323 111 475 251
kgp418674 33% 30 19 147 82 222 80 207 120 591 242
rs241451 26% 39 12 207 68 150 100 285 92 507 268
kgp6137749 40% 85 30 201 83 111 68 371 143 423 219
rs9501224 25% 39 11 211 70 149 100 289 92 509 270
kgp9296977 28% 53 16 178 68 167 96 284 100 512 260
rs2071469 31% 59 18 205 76 134 87 323 112 473 250
kgp10991488 39% 85 30 194 81 110 68 364 141 414 217
kgp12106435 15% 4 7 54 39 334 132 62 53 722 303
kgp9394249 1% 1 0 17 3 379 177 19 3 775 357
kgp4490237 4% 0 0 12 13 387 168 12 13 786 349
kgp3275166 1% 0 0 4 5 394 176 4 5 792 357
kgp7178883 3% 1 1 12 10 384 169 14 12 780 348
rs241443 25% 40 11 202 69 152 99 282 91 506 267
kgp5249257 28% 54 17 177 67 167 97 285 101 511 261
kgp721209 28% 54 17 177 67 167 97 285 101 511 261
kgp4209856 28% 53 17 178 68 167 95 284 102 512 258
kgp10626023 16% 17 9 140 41 242 131 174 59 624 303
kgp5162959 28% 54 17 177 67 166 97 285 101 509 261
kgp2033254 2% 0 0 4 8 394 173 4 8 792 354
kgp3509792 6% 1 1 31 19 367 161 33 21 765 341
b. Additive Model, Analysis of Candidate Genes (30) - replicated p < 0.05 (GALA, FORTE, and Combined cohorts)
GALA FORTE
Al- Al-
Armi- Al- lele Armi- Al- lele
tage lele Freq. tage lele Freq.
P- Odds Freq. (Non- P- Odds Freq. (Non-
Name Ch Gene valu Rat (Res Resp valu Rat (Res Resp
rs1894407 6 HLA-DOB/TAP2 0.002 1.77 42% 30% 0.02 1.72 40% 29%
rs1894406 6 HLA-DOB/TAP2 0.003 1.74 40% 29% 0.02 1.76 36% 25%
rs1894408 6 HLA-DOB/TAP2 0.003 1.72 42% 31% 0.01 1.82 41% 28%
rs2857103 6 TAP2 0.006 1.70 37% 27% 0.00 2.04 36% 22%
kgp10224254 6 HLA-DOB 0.006 1.63 42% 32% 0.04 1.58 39% 29%
rs241451 6 TAP2 0.006 1.69 37% 27% 0.01 1.86 35% 23%
rs9501224 6 TAP2 0.007 1.69 37% 27% 0.00 2.04 36% 22%
rs2071469 6 HLA-DOB 0.007 1.62 43% 32% 0.04 1.58 39% 29%
rs241443 6 TAP2 0.011 1.63 37% 27% 0.01 2.01 35% 22%
rs2621323 6 HLA-DOB/TAP2 0.019 1.56 37% 29% 0.00 2.07 36% 22%
rs241456 6 TAP2 0.021 1.55 31% 23% 0.01 2.00 30% 18%
rs2621321 6 HLA-DOB/TAP2 0.024 1.54 32% 23% 0.01 2.05 30% 18%
rs2857104 6 TAP2 0.024 1.54 32% 23% 0.01 2.03 30% 18%
rs2857101 6 TAP2 0.025 1.53 31% 23% 0.01 2.00 30% 18%
rs241446 6 TAP2 0.025 1.53 31% 23% 0.01 1.96 30% 18%
rs241454 6 TAP2 0.026 1.53 31% 23% 0.01 2.02 30% 18%
kgp974569 6 TAP2 0.028 1.52 31% 23% 0.01 2.02 30% 18%
rs241447 6 TAP2 0.028 1.52 31% 23% 0.01 2.01 30% 18%
rs241444 6 TAP2 0.028 1.52 31% 23% 0.01 2.00 30% 18%
rs2071472 6 HLA-DOB 0.029 1.49 35% 27% 0.02 1.79 33% 22%
rs2071470 6 HLA-DOB 0.029 1.49 35% 27% 0.02 1.79 33% 22%
rs241449 6 TAP2 0.033 1.50 31% 23% 0.01 1.99 30% 18%
rs241452 6 TAP2 0.033 1.50 31% 24% 0.01 2.01 30% 18%
rs241453 6 TAP2 0.034 1.50 31% 23% 0.01 2.02 30% 18%
rs241440 6 TAP2 0.034 1.50 31% 23% 0.01 1.96 30% 18%
kgp8036704 6 TAP2 0.035 1.50 31% 23% 0.01 2.02 30% 18%
kgp7747883 18 MBP 0.036 0.70 35% 43% 0.01 0.57 33% 45%
rs241445 6 TAP2 0.036 1.49 31% 24% 0.01 2.00 30% 18%
P1_M_06151 6 TAP2 0.037 1.49 31% 23% 0.01 2.02 30% 18%
rs241442 6 TAP2 0.039 1.48 31% 24% 0.01 2.02 30% 18%
kgp2388352 6 TAP2 0.042 1.47 31% 24% 0.01 2.02 30% 18%
kgp25543811 18 MBP 0.048 0.15 0% 2% 0.01 0.10 0% 2%
kgp4346717 18 MBP 0.049 0.15 0% 2% 0.01 ? 0% 2%
kgp3182607 6 PSMB9 0.049 0.15 0% 2% 0.02 0.23 1% 4%
rs241435 6 TAP2 0.049 0.15 0% 2% 0.02 0.23 1% 4%
kgp26271158 6 PSMB9 0.049 0.15 0% 2% 0.04 0.29 1% 4%
b. Additive Model, Analysis of Candidate Genes (30) - replicated p < 0.05
(GALA, FORTE, and Combined cohorts)
COMBINED
Al-
Armi- Al- lele
tage lele Freq. DD Dd dd
P- Odds Freq. (Non- DD (Con- Dd (Con- dd (Con-
Name valu Rati (Resp Resp (Cas trols (Cas trols) (Cas trols)
rs1894407 0.00011 1.73 41% 30% 57 16 213 75 128 90
rs1894406 0.00027 1.68 38% 27% 51 13 202 73 146 95
rs1894408 0.00010 1.73 41% 30% 58 16 211 74 127 89
rs2857103 0.00011 1.78 36% 25% 39 11 211 69 149 100
kgp10224254 0.00115 1.56 40% 31% 59 18 205 75 135 88
rs241451 0.00026 1.72 36% 26% 39 12 207 68 150 100
rs9501224 0.00013 1.77 36% 25% 39 11 211 70 149 100
rs2071469 0.00140 1.55 41% 31% 59 18 205 76 134 87
rs241443 0.00030 1.71 36% 25% 40 11 202 69 152 99
rs2621323 0.00033 1.69 37% 26% 43 12 207 71 149 97
rs241456 0.00086 1.66 31% 21% 32 9 180 59 187 113
rs2621321 0.00090 1.66 31% 22% 31 9 183 60 184 112
rs2857104 0.00099 1.65 31% 22% 31 9 183 60 185 112
rs2857101 0.00115 1.64 30% 21% 31 9 181 59 187 112
rs241446 0.00126 1.63 30% 21% 32 9 176 59 188 113
rs241454 0.00102 1.65 31% 22% 32 9 180 60 185 112
kgp974569 0.00112 1.64 31% 22% 32 9 180 60 186 112
rs241447 0.00111 1.64 31% 22% 32 9 180 60 184 111
rs241444 0.00122 1.63 31% 22% 32 9 180 60 187 112
rs2071472 0.00221 1.56 34% 25% 40 12 191 67 168 102
rs2071470 0.00221 1.56 34% 25% 40 12 191 67 168 102
rs241449 0.00135 1.63 30% 21% 32 9 175 58 188 112
rs241452 0.00142 1.62 31% 22% 32 9 179 60 186 111
rs241453 0.00131 1.63 31% 22% 32 9 179 60 187 112
rs241440 0.00179 1.61 30% 22% 32 9 177 60 189 112
kgp8036704 0.00155 1.63 30% 22% 29 9 183 60 186 112
kgp7747883 0.00086 0.64 34% 44% 43 33 181 92 174 56
rs241445 0.00156 1.62 31% 22% 32 9 179 60 187 111
P1_M_06151 0.00141 1.62 30% 22% 32 9 178 60 187 112
rs241442 0.00156 1.62 31% 22% 32 9 179 60 187 111
kgp2388352 0.00146 1.62 31% 22% 34 10 173 57 185 111
kgp25543811 0.00229 0.12 0% 2% 0 0 2 7 397 173
kgp4346717 0.00174 0.07 0% 2% 0 0 1 6 398 175
kgp3182607 0.00685 0.24 1% 2% 0 0 5 9 394 172
rs241435 0.00685 0.24 1% 2% 0 0 5 9 394 172
kgp26271158 0.01475 0.29 1% 2% 0 0 6 9 393 172
indicates data missing or illegible when filed
TABLE 5
Allelic Model, Analysis of Candidate Genes (30) (GALA, FORTE, and Combined cohorts)
GALA FORTE
Odds Al- Odds Al-
Gene Ratio Al- lele Ratio Al- lele
Loca- Fisher's (Minor lele Freq. Fisher's (Minor lele Freq.
Muta- tions Exact Al- Freq. (Con- Exact Al- Freq. (Con-
Name Ch Gene(s) tion (s) P lele) (Cases) trols) P lele) (Cases) trols)
kgp11795 6 ? ? ? 0.003 2.10 20% 11% 0.248 1.49 16% 11%
kgp51108 17 CCL5 Silent INTRON 0.003 0.00 0% 3% 1.000 ? 0% 0%
rs1894407 6 ? ? ? 0.003 1.68 42% 30% 0.0247 1.67 40% 29%
kgp89008 6 ? ? ? 0.003 2.00 20% 11% 0.248 1.47 16% 11%
kgp64748 6 TNF Silent INTRON 0.003 2.00 20% 11% 0.307 1.44 16% 12%
rs1894406 6 ? ? ? 0.004 1.66 40% 29% 0.0212 1.73 36% 25%
rs909253 6 LTA, LTA Silent, Sil INTRON 0.004 0.59 25% 36% 0.816 0.95 27% 28%
rs1894408 6 ? ? ? 0.005 1.64 42% 31% 0.0105 1.78 41% 28%
kgp93199 3 CCR5, CCR5 Silent, Sil INTRON 0.005 1.60 48% 37% 0.835 1.06 45% 43%
kgp92969 3 ? ? ? 0.005 1.66 37% 26% 0.514 1.16 35% 31%
kgp41867 6 LTA, LTA Missense EXON 0.005 0.60 25% 36% 0.816 0.94 27% 28%
kgp71788 18 SLC14A2 Silent INTRON 0.006 0.21 1% 5% 0.471 3.07 3% 1%
kgp92969 10 ? ? ? 0.006 0.21 1% 5% 0.0267 2.53 4% 2%
kgp12106 18 MBP, MBP Silent, Sil INTRON 0.006 0.50 9% 16% 0.089 0.54 7% 12%
kgp61377 3 CCR5, CCR5 Silent, Sil UTR 0.007 1.58 48% 37% 0.917 1.04 45% 44%
kgp10224 6 ? ? ? 0.007 1.59 42% 32% 0.053 1.56 39% 29%
kgp58541 18 NOL4, NOL4, Silent, Sil INTRON 0.008 0.15 1% 3% 1.000 1.33 3% 2%
kgp10991 3 CCR5, CCR5 Silent, Sil INTRON 0.008 1.58 48% 37% 0.755 1.07 45% 43%
kgp93942 18 MBP, MBP Silent, Sil INTRON 0.009 ? 3% 0% 0.725 0.81 2% 2%
kgp12268 3 ? ? ? 0.009 0.24 1% 5% 0.487 0.60 2% 3%
kgp26488 6 TAP1 Silent INTRON 0.009 0.24 1% 5% 1.000 1.83 1% 1%
kgp51629 3 CCR5, CCR5 Silent, Sil INTRON 0.009 1.60 37% 27% 0.383 1.24 35% 30%
kgp52492 3 CCR5, CCR5 Silent, Sil INTRON 0.009 1.61 37% 27% 0.384 1.22 35% 30%
kgp72120 3 CCR5, CCR5 Silent, Sil UTR 0.009 1.61 37% 27% 0.384 1.22 35% 30%
kgp42098 3 ? ? ? 0.009 1.61 37% 27% 0.584 1.14 35% 32%
rs2071469 6 HLA-DOB Silent UTR 0.009 1.57 43% 32% 0.053 1.56 39% 29%
rs241451 6 TAP2, TAP2 Silent, Sil INTRON 0.011 1.58 37% 17% 0.0144 1.80 35% 23%
rs2857103 6 TAP2 Silent INTRON 0.011 1.59 37% 27% 0.0057 1.94 36% 22%
kgp10626 18 NOL4, NOL4, Silent, Sil INTRON 0.011 1.73 24% 15% 0.0799 1.11 20% 18%
rs9501224 6 TAP2 Silent INTRON 0.012 1.57 37% 27% 0.0057 1.94 36% 22%
kgp44902 6 ? ? ? 0.013 0.29 2% 5% 1.000 1.83 1% 1%
kgp58475 4 IL15, IL15, IL1 Silent, Sil INTRON, E 0.014 0.10 0% 3% 1.000 1.53 1% 1%
kgp35097 18 NOL4, NOL4, Silent, Sil INTRON 0.014 0.39 3% 8% 0.127 3.14 5% 2%
rs3733904 5 ERAP2, ERAP Silent, Sil INTRON 0.016 1.61 30% 21% 0.176 1.45 24% 18%
kgp28530 18 SLC14A2 Silent INTRON 0.016 ? 2% 0% 1.000 1.22 2% 2%
Allelic Model, Analysis of Candidate Genes (30)
(GALA, FORTE, and Combined cohorts)
COMBINED
Odds Al-
Ratio Al- lele
Fisher's (Minor lele Freq. DD Dd dd
Exact Al- Freq. (Con- DD (Con- Dd (Con- dd (Con-
Name P lele) (Cases) trols) (Cases) trols) (Cases) trols) (Cases) trols)
kgp11795 0.0022 1.80 18% 11% 16 3 111 33 271 144
kgp51108 0.0046 0.07 0% 2% 0 0 1 6 398 175
rs1894407 0.0002 1.66 41% 30% 57 16 213 75 128 90
kgp89008 0.0033 1.73 18% 11% 16 3 112 35 270 143
kgp64748 0.0042 1.72 18% 11% 16 3 112 35 270 142
rs1894406 0.0004 1.63 38% 27% 51 13 202 73 146 95
rs909253 0.0112 0.70 26% 33% 30 19 146 83 220 79
rs1894408 0.0002 1.67 41% 30% 58 16 211 74 127 89
kgp93199 0.0182 1.36 47% 39% 84 30 203 82 110 69
kgp92969 0.0086 1.44 36% 28% 53 16 178 68 167 96
kgp41867 0.0136 0.71 26% 33% 30 19 147 82 222 80
kgp71788 0.13 0.52 2% 3% 1 1 12 10 384 169
kgp92969 0.34 0.70 3% 4% 0 0 20 13 376 168
kgp12106 0.0004 0.49 8% 15% 4 7 54 39 334 132
kgp61377 0.0255 1.34 47% 40% 85 30 201 83 111 68
kgp10224 0.0013 1.54 40% 31% 59 18 205 75 135 88
kgp58541 0.28 0.61 2% 3% 0 0 15 11 383 170
kgp10991 0.0208 1.35 47% 39% 85 30 194 81 110 68
kgp93942 0.10 2.92 2% 1% 1 0 17 3 379 177
kgp12268 0.0075 0.36 2% 4% 0 0 13 16 386 165
kgp26488 0.0235 0.38 1% 4% 0 0 11 13 388 168
kgp51629 0.0087 1.45 36% 28% 54 17 177 67 166 97
kgp52492 0.0087 1.44 36% 28% 54 17 177 67 167 97
kgp72120 0.0087 1.44 36% 28% 54 17 177 67 167 97
kgp42098 0.0153 1.40 36% 28% 53 17 178 68 167 95
rs2071469 0.0017 1.52 41% 31% 59 18 205 76 134 87
rs241451 0.0004 1.64 36% 26% 39 12 207 68 150 100
rs2857103 0.0003 1.68 36% 25% 39 11 211 69 149 100
kgp10626 0.0326 1.43 22% 16% 17 9 140 41 242 131
rs9501224 0.0003 1.67 36% 25% 39 11 211 70 149 100
kgp44902 0.0291 0.41 2% 4% 0 0 12 13 387 168
kgp58475 0.13 0.39 1% 2% 0 0 6 7 390 174
kgp35097 0.23 0.70 4% 6% 1 1 31 19 367 161
rs3733904 0.0102 1.49 27% 20% 37 4 141 64 221 113
kgp28530 0.08 3.92 2% 1% 0 0 17 2 382 179
b. Allelic Model, Analysis of Candidate Genes (30) - replicated p < 0.05 (GALA, FORTE, and Combined cohorts)
GALA FORTE
Al- Al-
Gene Odds Al- lele Odds Al- lele
Loca- Ratio lele Freq. Ratio lele Freq.
tions Fisher's (Minor Freq. (Con- Fisher's (Minor Freq. (Con-
Name Gene(s) Mutat (s) Exact Alle (Cas trols Exact Allel (Cas trols)
rs1894407 6 ? ? ? 0.003 1.68 42% 30% 0.0247 1.67 40% 29%
rs1894406 6 ? ? ? 0.004 1.66 40% 29% 0.0212 1.73 36% 25%
rs1894408 6 ? ? ? 0.005 1.64 42% 31% 0.0105 1.78 41% 28%
rs24151 6 TAP2, TAP2 Silent, Sile INTRON 0.011 1.58 37% 27% 0.0144 1.80 35% 23%
rs2857103 6 TAP2 Silent INTRON 0.011 1.59 37% 27% 0.0057 1.94 36% 22%
rs9501224 6 TAP2 Silent INTRON 0.012 1.57 37% 27% 0.0057 1.94 36% 22%
rs241443 6 TAP2, TAP2 Silent, Sile INTRON, E 0.018 1.54 37% 27% 0.0071 1.94 35% 22%
rs241456 6 TAP2, TAP2 Silent, Sile INTRON 0.023 1.53 31% 23% 0.0104 1.93 30% 18%
rs241446 6 TAP2, TAP2 Silent, Sile INTRON, E 0.028 1.52 31% 23% 0.0140 1.90 30% 18%
rs2857101 6 TAP2, TAP2 Silent, Sile INTRON 0.029 1.52 31% 23% 0.0141 1.91 30% 18%
rs241454 6 TAP2, TAP2 Silent, Sile INTRON 0.029 1.51 31% 23% 0.0103 1.95 30% 18%
rs2621321 6 ? ? ? 0.029 1.52 32% 23% 0.0103 1.95 30% 18%
rs2857104 6 TAP2 Silent INTRON 0.029 1.52 32% 23% 0.0104 1.93 30% 18%
rs2621323 6 ? ? ? 0.030 1.48 37% 29% 0.0041 2.01 36% 22%
rs241449 6 TAP2, TAP2 Silent, Sy INTRON, E 0.034 1.50 31% 23% 0.0104 1.92 30% 18%
rs2071472 6 HLA-DOB Silent INTRON 0.035 1.47 35% 27% 0.0246 1.74 33% 22%
rs2071470 6 HLA-DOB Silent UTR 0.035 1.47 35% 27% 0.0246 1.74 33% 22%
rs241447 6 TAP2, TAP2 Silent, Mis INTRON, E 0.037 1.50 31% 23% 0.0102 1.94 30% 18%
kgp974569 6 TAP2, TAP2 Silent, Sile INTRON 0.037 1.50 31% 23% 0.0103 1.95 30% 18%
rs241444 6 TAP2, TAP2 Silent, Sile INTRON, E 0.037 1.50 31% 23% 0.0104 1.93 30% 18%
rs241452 6 TAP2, TAP2 Silent, Sile INTRON 0.037 1.48 31% 24% 0.0103 1.94 30% 18%
rs241453 6 TAP2, TAP2 Silent, Sile INTRON 0.037 1.48 31% 23% 0.0103 1.95 30% 18%
rs241440 6 TAP2, TAP2 Silent, Sile INTRON 0.037 1.48 31% 23% 0.0140 1.90 30% 18%
kgp7747883 18 MBP, MBP Silent, Sile INTRON 0.043 0.70 35% 43% 0.0129 0.59 33% 45%
kgp2388352 6 TAP2, TAP2 Synonym EXON 0.043 1.47 31% 24% 0.0076 1.99 30% 18%
rs241445 6 TAP2, TAP2 Silent, Sile INTRON, E 0.045 1.48 31% 24% 0.0104 1.93 30% 18%
P1_M_0615 6 TAP2, TAP2 ? INTRON 0.045 1.47 31% 23% 0.0103 1.95 30% 18%
kgp8036704 6 TAP2, TAP2 Silent, Sile INTRON 0.045 1.47 31% 23% 0.0141 1.91 30% 18%
rs241442 6 TAP2, TAP2 Silent, Sile INTRON, E 0.045 1.46 31% 24% 0.0103 1.95 30% 18%
kgp8702370 3 DNAJC13 Silent INTRON 0.049 1.68 15% 9% 0.0079 2.88 15% 6%
b. Allelic Model, Analysis of Candidate Genes (30) - replicated p < 0.05
(GALA, FORTE, and Combined cohorts)
COMBINED
Al-
Odds Al- lele
Ratio lele Freq. DD Dd dd
Fisher's (Minor Freq. (Con- DD (Con- Dd (Con- dd (Con-
Name Exact Allel (Cas trol (Cases) trol (Cases) trol (Cases) trol
rs1894407 0.0002 1.66 41% 30% 57 16 213 75 128 90
rs1894406 0.0004 1.63 38% 27% 51 13 202 73 146 95
rs1894408 0.0002 1.67 41% 30% 58 16 211 74 127 89
rs24151 0.0004 1.64 36% 26% 39 12 207 68 150 100
rs2857103 0.0003 1.68 36% 25% 39 11 211 69 149 100
rs9501224 0.0003 1.67 36% 25% 39 11 211 70 149 100
rs241443 0.0005 1.64 36% 25% 40 11 202 69 152 99
rs241456 0.0011 1.63 31% 21% 32 9 180 59 187 113
rs241446 0.0014 1.61 30% 21% 32 9 176 59 188 113
rs2857101 0.0014 1.61 30% 21% 31 9 181 59 187 112
rs241454 0.0011 1.62 31% 22% 32 9 180 60 185 112
rs2621321 0.0011 1.62 31% 22% 31 9 183 60 184 112
rs2857104 0.0012 1.61 31% 22% 31 9 183 60 185 112
rs2621323 0.0006 1.62 37% 26% 43 12 207 71 149 97
rs241449 0.0016 1.61 30% 21% 32 9 175 58 188 112
rs2071472 0.0026 1.53 34% 25% 40 12 191 67 168 102
rs2071470 0.0026 1.53 34% 25% 40 12 191 67 168 102
rs241447 0.0014 1.61 31% 22% 32 9 180 60 184 111
kgp974569 0.0014 1.61 31% 22% 32 9 180 60 186 112
rs241444 0.0014 1.60 31% 22% 32 9 180 60 187 112
rs241452 0.0018 1.59 31% 22% 32 9 179 60 186 111
rs241453 0.0014 1.60 31% 22% 32 9 179 60 187 112
rs241440 0.0022 1.58 30% 22% 32 9 177 60 189 112
kgp7747883 0.0010 0.65 34% 44% 43 33 181 92 174 56
kgp2388352 0.0014 1.61 31% 22% 34 10 173 57 185 111
rs241445 0.0018 1.59 31% 22% 32 9 179 60 187 111
P1_M_0615 0.0018 1.60 30% 22% 32 9 178 60 187 112
kgp8036704 0.0022 1.58 30% 22% 29 9 183 60 186 112
rs241442 0.0018 1.59 31% 22% 32 9 179 60 187 111
kgp8702370 0.0012 1.98 15% 8% 9 0 100 29 290 151
indicates data missing or illegible when filed
In some embodiments genetic markers presented in Tables 4 and 5 are identified as predictive of response to glatiramer acetate if the p-value for the Combined cohort is less than about 0.05, less than about 0.01, less than about 0.005, less than about 0.001, less than about 0.0005 or less than about 10−4.
Example 7 Analysis Part 3—Analysis of Candidate Genes (180) The third analysis was limited to a selected set of genetic variants in 180 priority candidate genes (25,461 variants).
Results for Standard Response Definition, 180 Candidate Genes Selected a priori for Additive and Allelic models are presented in tables 6-7, respectively.
In some embodiments genetic markers presented in Tables 6 and 7 are identified as predictive of response to glatiramer acetate if the p-value for the GALA cohort is less than about 0.05, less than about 0.01, less than about 0.005, less than about 0.001, less than about 0.0005 or less than about 10−4.
In some embodiments genetic markers presented in Tables 6 and 7 are identified as predictive of response to glatiramer acetate if the p-value for the FORTE cohort is less than about 0.05, less than about 0.01 or less than about 0.005.
In some embodiments genetic markers presented in Tables 6 and 7 are identified as predictive of response to glatiramer acetate if the p-value for the Combined cohort is less than about 0.05, less than about 0.01, less than about 0.005, less than about 0.001, less than about 0.0005 or less than about 10−4.
TABLE 6
Additive Model, Analysis of Candidate Genes (180) (GALA, FORTE, and Combined cohorts)
GALA FORTE Combined
Regres- Regres- Regres-
Gene Armi- sion Armi- sion Armi- sion DD Dd dd
Posi- Muta- Loca- tage Odds tage Odds tage Odds DD (Con- Dd (Con- dd (Con-
Name Ch tion Gene(s) tion tions(s) P Ratio P Ratio P Ratio (Cases) trols) (Cases) trols) (Cases) trols)
rs1894407 6 32787036 ? ? ? 0.00175175 1.8 0.01812361 1.7 0.00010632 1.7 57 16 213 75 128 90
rs1894406 6 32787056 ? ? ? 0.00262814 1.7 0.01731899 1.8 0.00026627 1.7 51 13 202 73 146 95
rs1894408 6 32786833 ? ? ? 0.00302235 1.7 0.00929977 1.8 9.82E−05 1.7 58 16 211 74 127 89
kgp6599438 20 40843626 PTPRT, Silent, INTRON 0.003702 0.2 0.01551449 0.3 0.00024816 0.3 0 0 11 18 386 163
PTPRT Silent
kgp293787 20 40905098 PTPRT, Sllent, INTRON 0.00486183 0.2 0.02186627 0.4 0.00254833 0.4 0 2 15 15 384 164
PTPRT Silent
rs2857103 6 32791299 TAP2 Silent INTRON 0.00572178 1.7 0.00412662 2.0 0.00011314 1.8 39 11 211 69 149 100
kgp10224254 6 32785904 ? ? ? 0.0058474 1.6 0.04442021 1.6 0.001151 1.6 59 18 205 75 135 88
rs241451 6 32796480 TAP2, TAP2 Silent, INTRON 0.00625568 1.7 0.01125399 1.9 0.00025798 1.7 39 12 207 68 150 100
Silent
rs9501224 6 32792910 TAP2 Silent INTRON 0.00652648 1.7 0.00412662 2.0 0.00013242 1.8 39 11 211 70 149 100
rs2071469 6 32784783 HLA-DOB Silent UTR 0.00676044 1.6 0.04442021 1.6 0.00139647 1.6 59 18 205 76 134 87
rs10162089 13 31316738 ALOX5AP, Silent, INTRON 0.007794 1.6 0.0315509 1.6 0.00139566 1.5 96 24 190 88 110 67
ALOX5AP Silent
rs241443 6 32797115 TAP2, TAP2 Silent, INTRON, 0.01054389 1.6 0.00527858 2.0 0.0003017 1.7 40 11 202 69 152 99
Silent EXON
rs3218328 22 37524008 IL2RB Silent UTR 0.01094804 0.2 0.01393817 0.1 0.00029615 0.1 0 0 3 10 395 169
kgp5334779 6 32628420 HLA-DQB1, Silent, INTRON 0.01680233 1.5 0.02742446 1.7 0.00187388 1.6 50 10 199 83 148 87
HLA-DQB1 Silent
kgp10632945 20 4682507 ? ? ? 0.0187382 0.6 0.03477091 0.6 0.00125431 0.6 10 11 118 70 270 100
rs2621323 6 32788707 ? ? ? 0.0189772 1.6 0.00308945 2.1 0.00033291 1.7 43 12 207 71 149 97
rs1410779 9 5083173 JAK2 Silent INTRON 0.01926688 0.6 0.01286783 0.5 0.00173172 0.6 8 10 112 66 277 105
kgp4479467 6 32629331 HLA-DQB1, Silent, INTRON 0.02026789 1.5 0.01594443 1.8 0.00124971 1.6 54 11 195 82 147 88
HLA-DQB1 Silent
rs241456 6 32795965 TAP2, TAP2 Silent, INTRON 0.02123306 1.6 0.00854177 2.0 0.00086275 1.7 32 9 180 59 187 113
Silent
rs2621321 6 32769490 ? ? ? 0.02375031 1.5 0.00719304 2.0 0.00090026 1.7 31 9 183 60 184 112
rs2857104 6 32790167 TAP2 Silent INTRON 0.02375031 1.5 0.00788787 2.0 0.00098748 1.7 31 9 183 60 185 112
rs2857101 6 32794676 TAP2, TAP2 Silent, INTRON 0.02480642 1.5 0.00932686 2.0 0.0011476 1.6 31 9 181 59 187 112
Silent
rs241446 6 32796967 TAP2, TAP2 Silent, INTRON, 0.02486364 1.5 0.0108596 2.0 0.00125819 1.6 32 9 176 59 188 113
Silent EXON
kgp4898179 6 32629347 HLA-DQB1, Silent, INTRON 0.02526492 1.5 0.01868249 1.8 0.0019063 1.6 54 11 195 83 148 87
HLA-DQB1 Silent
rs241454 6 32796144 TAP2, TAP2 Silent, INTRON 0.02565201 1.5 0.00790448 2.0 0.00101933 1.6 32 9 180 60 185 112
Silent
kgp9699754 10 79358319 KCNMA1, Silent, INTRON 0.02698903 ? 0.04107681 ? 0.00174374 ~In- 0 0 21 0 377 179
KCNMA1, Silent, finity
KCNMA1, Silent,
KCNMA1 Silent
kgp974569 6 32796057 TAP2, TAP2 Silent, INTRON 0.02848011 1.5 0.00780448 2.0 0.00111661 1.6 32 9 180 60 186 112
Silent
rs241447 6 32796751 TAP2, TAP2 Silent, INTRON, 0.02848011 1.5 0.00834304 2.0 0.00110846 1.6 32 9 180 60 184 111
Misse EXON
rs241444 6 32797109 TAP2, TAP2 Silent, INTRON, 0.02848011 1.5 0.00854177 2.0 0.00122194 1.6 32 9 180 60 187 112
Silent EXON
GALA FORTE Combined
Gene Regres- Regre- Regres-
Loca- Armi- sion ssion sion DD Dd dd
tions tage Odds Odds Odds DD (Con- Dd (Con- dd (Con-
Name Ch Positi Gene Mutat (s) P Rati Armit Rati Armita Ratio (Cases trols) (Cases trols) (Cases trols)
rs2071472 6 32784620 HLA-DOB Silent INTRON 0.029144 1.5 0.018629 1.8 0.002212 1.6 40 12 191 67 168 102
rs2071470 6 32784753 HLA-DOB Silent UTR 0.029144 1.5 0.018629 1.8 0.002212 1.6 40 12 191 67 168 102
kgp22778566 7 1960337 MAD1L1, Silent, INTRON 0.030998 1.6 0.02869 1.9 0.007 1.6 19 4 156 53 220 117
Si
kgp5032617 13 31287981 ALOX5AP Silent INTRON 0.031116 0.7 0.043799 0.6 0.00444 0.7 23 15 131 79 244 87
rs4769060 13 31337877 ALOX5AP Silent, INTRON 0.031432 1.4 0.031343 1.6 0.004432 1.4 87 22 189 88 123 71
Si
rs241449 6 32796653 TAP2, TA Silent, INTRON 0.032511 1.5 0.009222 2.0 0.001348 1.6 32 9 175 58 188 112
Sy
rs241452 6 32796346 TAP2, TA Silent, INTRON 0.033124 1.5 0.008432 2.0 0.001424 1.6 32 9 179 60 186 111
Si
rs241453 6 32796226 TAP2, TA Silent, INTRON 0.033989 1.5 0.007804 2.0 0.001311 1.6 32 9 179 60 187 112
Si
rs241440 6 32797361 TAP2, TA Silent, INTRON 0.033989 1.5 0.01086 2.0 0.001795 1.6 32 9 177 60 189 112
Si
kgp304921 20 14017077 MACRO Silent INTRON 0.034256 0.5 0.015134 0.3 0.0008 0.4 2 2 19 23 373 154
kgp8036704 6 32796521 TAP2, TA Silent, INTRON 0.035126 1.5 0.008613 2.0 0.001563 1.6 29 9 183 60 186 112
Si
kgp6440506 13 31320543 ALCC5AP Silent, INTRON 0.035201 0.7 0.024964 0.6 0.007941 0.7 81 45 175 95 138 40
Si
kgp7747883 18 74804250 MBP, MB Silent, INTRON 0.035519 0.7 0.00982 0.6 0.000864 0.6 43 33 181 92 174 56
Si
rs241445 6 32797072 TAP2, TA Silent, INTRON 0.035654 1.5 0.008542 2.0 0.001565 1.6 32 9 179 60 187 111
Si
rs10815160 9 5116616 JAK2 Silent INTRON 0.035753 0.7 0.036927 0.6 0.009339 0.7 19 14 124 71 248 93
P1_M_061510_6_ 6 32795505 TAP2, TA ? INTRON 0.035607 1.5 0.007804 2.0 0.001406 1.6 32 9 178 60 187 112
rs9671182 13 31321138 ALOX5AP Silent, INTRON 0.038955 0.7 0.027648 0.6 0.008781 0.7 82 45 180 96 136 39
Si
rs241442 6 32797168 TAP2, TA Silent, INTRON 0.039353 1.5 0.007804 2.0 0.001555 1.6 32 9 179 60 187 111
Si
rs4356336 13 31319546 ALOX5AP Silent, INTRON 0.039764 0.7 0.027648 0.6 0.008948 0.7 82 46 181 96 136 40
Si
kgp2388352 6 32797297 TAP2, TA Synonym EXON 0.042477 1.5 0.007057 2.0 0.001455 1.6 34 10 173 57 185 111
rs11147439 13 31325613 ALOX5AP Silent, INTRON 0.043409 0.7 0.021636 0.6 0.008096 0.7 81 45 180 96 138 40
Si
rs2043136 3 30720304 TGFBR2, Silent, INTRON 0.044239 1.5 0.037491 1.7 0.004107 1.5 38 7 167 67 191 106
Si
kgp11281589 7 1941003 MAD1L1, Silent, INTRON 0.045301 1.5 0.042434 1.9 0.017566 1.5 19 5 155 55 219 117
Si
kgp5441587 6 32827356 PSMB9 Silent UTR 0.045581 0.1 0.01974 0.2 0.006103 0.2 0 0 5 9 394 169
kgp97310 9 5122932 JAK2 Silent INTRON 0.045767 0.7 0.019889 0.6 0.007785 0.7 17 14 125 70 256 97
rs4360791 13 31318020 ALOX5AP, Silent, INTRON 0.046466 0.7 0.029161 0.6 0.008598 0.7 85 48 181 94 133 39
Si
kgp25543811 18 74774894 MBP, MB Silent, INTRON 0.048109 0.1 0.013651 0.1 0.002288 0.1 0 0 2 7 397 173
Si
kgp23672937 7 18685891 HDAC9, Silent, INTRON 0.049393 0.1 0.009967 ? 0.00174 0.1 0 0 1 6 398 175
Si
kgp4346717 18 74810199 MBP, MB Silent, INTRON 0.049393 0.1 0.009967 ? 0.00174 0.1 0 0 1 6 398 175
Si
rs241435 6 32798243 TAP2, TA Silent, INTRON 0.049393 0.1 0.01974 0.2 0.006849 0.2 0 0 5 9 394 172
Si
kgp3182607 6 32823948 PSMB9 Missens EXON 0.049393 0.1 0.01974 0.2 0.006849 0.2 0 0 5 9 394 172
kgp26271158 6 32823393 PSMB9 Silent INTRON 0.049393 0.1 0.041512 0.3 0.014748 0.3 0 0 6 9 393 172
rs4254166 13 31322949 ALOX5AP, Silent, INTRON 0.049706 0.7 0.023968 0.6 0.009958 0.7 81 45 182 96 136 40
Si
kgp2715873 13 31320249 ALOX5AP, Silent, INTRON 0.049706 0.7 0.027648 0.6 0.011301 0.7 82 45 181 96 136 40
Si
rs9670531 13 31321069 ALOX5AP, Silent, INTRON 0.049706 0.7 0.027648 0.6 0.011301 0.7 82 45 181 96 136 40
Si
indicates data missing or illegible when filed
TABLE 7
Allelic Model, Analysis of Candidate Genes (180) (GALA, FORTE, and Combined cohorts)
GALA FORTE COMBINED
Gene Odds Odds Odds
Loca- Ratio Ratio Ratio
Chromo- tions Fisher's (Minor Fisher's (Minor Fisher's (Minor
Name some Positi Gene( Mutat (s) Exact Allel Exact Allel Exact Allel
rs1894408 6 32786833 ? ? ? 0.005009 1.6 0.010522 1.8 0.000175 1.7
rs1894407 6 32787036 ? ? ? 0.003054 1.7 0.02471 1.7 0.000185 1.7
rs2857103 6 32791299 TAP2 Silent INTRON 0.011421 1.6 0.005691 1.9 0.006254 1.7
rs9501224 6 32792910 TAP2 Silent INTRON 0.011794 1.6 0.005691 1.9 0.000267 1.7
rs1894406 6 32787056 ? ? ? 0.003758 1.7 0.02118 1.7 0.000411 1.6
rs241451 6 32796480 TAP2, TA Silent, INTRON 0.011396 1.6 0.014428 1.8 0.000429 1.6
Sil
rs241443 6 32797115 TAP2, TA Silent, INTRON, 0.018211 1.5 0.007128 1.9 0.000515 1.6
Sil E
kgp9699754 10 79358319 KCNMA1, Silent, INTRON 0.028334 ? 0.045622 ? 0.000521 ?
Sil
rs2621323 6 32788707 ? ? ? 0.030375 1.5 0.004125 2.0 0.000593 1.6
kgp6599438 20 40843626 PTPRT, PT Silent, INTRON 0.005974 0.2 0.025262 0.3 0.000764 0.3
Sil
rs3218328 22 37524008 1L2RB Silent UTR 0.015946 0.2 0.041488 0.1 0.000821 0.1
kgp304921 20 14017077 MACROD Silent INTRON 0.029064 0.5 0.03 0.3 0.000838 0.4
kgp7747883 18 74804250 MBP, MB Silent, INTRON 0.042737 0.7 0.012878 0.6 0.001016 0.7
Sil
rs241456 6 32795965 TAP2, TAP Silent, INTRON 0.023192 1.5 0.010406 1.9 0.601099 1.6
Sil
rs2621321 6 32789480 ? ? ? 0.029482 1.5 0.010334 1.9 0.001137 1.6
rs241454 6 32796144 TAP2, TAP Silent, INTRON 0.029427 1.5 0.010334 1.9 0.00114 1.6
Sil
rs2857104 6 32790167 TAP2 Silent INTRON 0.029482 1.5 0.010406 1.9 0.001153 1.6
kgp8702370 3 1.32E+08 DNAJC13 Silent INTRON 0.04888 1.7 0.007895 2.9 0.001162 2.0
kgp2388352 6 32797297 TAP2, TAP Synonym EXON 0.043348 1.5 0.007574 2.0 0.001352 1.6
rs10162089 13 31316738 ALOXSAP, Silent, INTRON 0.008386 1.6 0.028565 1.6 0.001361 1.5
Sil
rs241446 6 32796967 TAP2, TAP Silent, INTRON, 0.028483 1.5 0.013955 1.9 0.001374 1.6
Sil E
rs2857101 6 32794676 TAP2, TAP Silent, INTRON 0.028792 1.5 0.014056 1.9 0.001387 1.6
Sil
rs241447 6 32796751 TAP2, TAP Silent, INTRON, 0.036579 1.5 0.010205 1.9 0.001413 1.6
Mis E
kgp974569 6 32796057 TAP2, TAP Silent, INTRON 0.036579 1.5 0.010334 1.9 0.001428 1.6
Sil
rs241444 6 32797109 TAP2, TAP Silent, INTRON, 0.036579 1.5 0.010406 1.9 0.001439 1.6
Sil E
rs241453 6 32796226 TAP2, TAP Silent, INTRON 0.036822 1.5 0.010334 1.9 0.001443 1.6
Sil
rs241449 6 32796653 TAP2, TAP Silent, INTRON, 0.03449 1.5 0.010436 1.9 0.00165 1.6
Syn E
rs241452 6 32796346 TAP2, TAP Silent, INTRON 0.036767 1.5 0.010309 1.9 0.001782 1.6
Sile
P1_M_061510_ 6 32795505 TAP2, TAP ? INTRON 0.044866 1.5 0.010334 1.9 0.001787 1.6
kgp4479467 6 32629331 HLA-DQB1 Silen, Sile INTRON 0.021213 1.5 0.022971 1.7 0.001788 1.5
rs241445 6 32797072 TAP2, TAP Silent, INTRON, 0.044862 1.5 0.010406 1.9 0.001797 1.6
Sile E
rs241402 6 32797168 TAP2, TAP Silent, INTRON, 0.045133 1.5 0.010334 1.9 0.001797 1.6
Sile E
kgp10632945 20 4682507 ? ? ? 0.020364 0.6 0.047361 0.6 0.001896 0.6
rs241440 6 32797361 TAP2, TAP Silent, INTRON 0.036822 1.5 0.013955 1.9 0.002245 1.6
Sile
kgp8036704 6 32796521 TAP2, TAP Silent, INTRON 0.044866 1.5 0.014056 1.9 0.002245 1.6
Sile
rs1410779 9 5083173 JAK2 Silent INTRON 0.02267 0.6 0.019785 0.6 0.002473 0.6
kgp9293787 20 40905098 PTPRT, PT Silent, INTRON 0.003474 0.1 0.039188 0.4 0.002484 0.3
Sile
rs2071472 6 32784620 HLA-DOB Silent INTRON 0.034998 1.5 0.024565 1.7 0.002622 1.5
rs2071470 6 32784753 HLA-DOB Silent UTR 0.034998 1.5 0.024565 1.7 0.002622 1.5
kgp5334779 6 32628420 HLA-DQB1 Silent, INTRON 0.020701 1.5 0.048854 1.6 0.002715 1.5
Sile
kgp4898179 6 32629347 HLA-DQB1 Silent, INTRON 0.026883 1.5 0.029479 1.7 0.002798 1.5
Sile
rs4769060 13 31337877 ALOX5AP, Silent, INTRON 0.032101 1.4 0.035596 1.6 0.003977 1.5
Sile
rs3803277 13 31318308 ALOX5AP, Silent, INTRON 0.048212 0.7 0.013126 0.6 0.00521 0.7
Sile
kgp5440506 13 31320543 ALOX5AP, Silent, INTRON 0.038212 0.7 0.021949 0.6 0.007278 0.7
Sile
rs11147439 13 31325643 ALOX5AP, Silent, INTRON 0.047187 0.7 0.022726 0.6 0.007532 0.7
Sile
kgp97310 9 5122932 JAK2 Silent INTRON 0.041273 0.7 0.023546 0.6 0.007654 0.7
rs4360791 13 31318020 ALOX5AP, Silent, INTRON 0.047959 0.7 0.022937 0.6 0.007655 0.7
Sile
kgp22778566 7 1950337 MAD1L1, Silent, INTRON 0.041523 1.5 0.038052 1.8 0.008717 1.5
Sile
rs9671182 13 31321138 ALOX5AP, Silent, INTRON 0.038607 0.7 0.029703 0.6 0.008926 0.7
Sile
rs4356336 13 31319546 ALOX5AP, Silent, INTRON 0.039248 0.7 0.029703 0.6 0.009084 0.7
Sile
rs10815160 9 5116616 JAK2 Silent INTRON 0.040396 0.6 0.043646 0.6 0.009679 0.7
COMBINED
Al-
Al- lele
lele Freq. DD Dd dd
Freq. (Con- DD (Con- Dd (Con- dd (Con-
Name (Case tro (Cas trols) (Cas trols); (Cas trols)
rs1894408 0.41 0.30 58 16 211 74 127 89
rs1894407 0.41 0.30 57 16 213 75 128 90
rs2857103 0.36 0.25 39 11 211 69 149 100
rs9501224 0.36 0.25 39 11 211 70 149 100
rs1894406 0.38 0.27 51 13 202 73 146 95
rs241451 0.36 0.26 39 12 207 68 150 100
rs241443 0.36 0.25 40 11 202 69 152 99
kgp9699754 0.03 0.00 0 0 21 0 377 179
rs2621323 0.37 0.26 43 12 207 71 149 97
kgp6599438 0.01 0.05 0 0 11 18 386 163
rs3218328 0.06 0.03 0 0 3 10 395 169
kgp304921 0.03 0.08 2 2 19 23 373 154
kgp7747883 0.34 0.44 43 33 181 92 174 56
rs241456 0.31 0.21 32 9 180 59 187 113
rs2621321 0.31 0.22 31 9 183 60 184 112
rs241454 0.31 0.22 32 9 180 60 185 112
rs2857104 0.31 0.22 31 9 183 60 185 112
kgp8702370 0.15 0.08 9 0 100 29 290 151
kgp2388352 0.31 0.22 34 10 173 57 185 111
rs10162089 0.48 0.38 96 24 190 68 110 67
rs241446 0.30 0.21 32 9 176 59 188 113
rs2857101 0.30 0.21 31 9 181 59 187 112
rs241447 0.31 0.22 32 9 180 60 184 111
kgp974569 0.31 0.22 32 9 180 60 186 112
rs241444 0.31 0.22 32 9 180 60 187 112
rs241453 0.31 0.22 32 9 179 60 187 112
rs241449 0.30 0.21 32 9 175 58 188 112
rs241452 0.31 0.22 32 9 179 60 186 111
P1_M_061510_ 0.30 0.22 32 9 178 60 187 112
kgp4479467 0.38 0.29 54 11 195 82 147 88
rs241445 0.31 0.22 32 9 179 60 187 111
rs241402 0.31 0.22 32 9 179 60 187 111
kgp10632945 0.17 0.25 10 11 118 70 270 100
rs241440 0.30 0.22 32 9 177 60 189 112
kgp8036704 0.30 0.22 29 9 183 60 186 112
rs1410779 0.16 0.24 8 10 112 66 277 105
kgp9293787 0.02 0.05 0 2 15 15 384 164
rs2071472 0.34 0.25 40 12 191 67 168 102
rs2071470 0.34 0.25 40 12 191 67 168 102
kgp5334779 0.38 0.29 50 10 199 83 148 87
kgp4898179 0.38 0.29 54 11 195 83 148 87
rs4769060 0.45 0.36 87 22 189 88 123 71
rs3803277 0.43 0.52 83 47 180 95 136 39
kgp5440506 0.43 0.51 81 45 175 95 138 40
rs11147439 0.43 0.51 81 45 180 96 138 40
kgp97310 0.20 0.27 17 14 125 70 256 97
rs4360791 0.44 0.52 85 48 181 94 133 39
kgp22778566 0.25 0.18 19 4 156 83 220 117
rs9671182 0.43 0.52 82 45 180 96 136 39
rs4356336 0.43 0.52 82 46 181 95 136 40
rs10815160 0.21 0.28 19 14 124 71 248 93
indicates data missing or illegible when filed
Example 8 Analysis Part 4—Genome Wide Analysis A full genome-wide analysis was then conducted (4 M variants). Power (80%) with Bonferroni statistical correction to identify significant genetic associations with an odds ratio >7, for variants with an allele frequency greater than 10%. (Or rare alleles (5%) with an odds ratio >11). Approximately 4,200 variants were selected for analysis in stage 2 (replication) (P<0.001).
Replication Cohort (n=262: 201 R vs. 61 NR)—In the second stage of analysis, variants selected in the discovery cohort were analyzed to identify replicating associations in the FORTE replication cohort associated with good response vs. poor response. Based upon an analysis of an estimated 4,200 variants, there is statistical power (80%) with Bonferroni correction to identify significant genetic associations with an odds ratio >6.5, for variants with an allele frequency greater than 5%.
Combined Cohorts (n=580: 399 R vs. 111 NR)—In the third stage of the analysis, the combined GALA and FORTE cohorts were analyzed identify variants associated with response/non-response using a full genome-wide analysis (4 M variants).
Results for Standard Response Definition, Genome Wide Analysis for Additive and Allelic models are presented in tables 8-9, respectively.
In some embodiments genetic markers presented in Tables 8 and 9 are identified as predictive of response to glatiramer acetate if the p-value for the GALA cohort is less than about 0.001, less than about 0.0005, less than about 10−4 or less than about 5*10−5.
In some embodiments genetic markers presented in Tables 8 and 9 are identified as predictive of response to glatiramer acetate if the p-value for the FORTE cohort is less than about 0.05, less than about 0.01, less than about 0.005, less than about 0.001 or less than about 0.0005.
TABLE 8
GALA FORTE
Re- Al- Re-
Gene gres- Al- lele gres- Al-
Loca- Armi- sion lele Freq. Armi- sion lele
Posi- tions tage Odds Freq. (Con- tage Odds Freq.
Name Ch tion Gene Mutati (s) P Rat (Cases) trol P Rat (Cas
Additive Model, Genome Wide Analysis, p-value sorted by GALA cohort (GALA, FORTE, and Combined cohorts)
kgp541056 1 65738507 DNAJC6 Silent INTRON 2.75E−05 0.44 0.18 0.33 3.24E−02 1.79 0.26
rs9817308 3 124182136 KALRN, Silent, INTRON 2.85E−05 0.49 0.41 0.58 2.64E−02 0.62 0.45
KA Sile
rs1749972 1 65736258 DNAJC6 Silent INTRON 3.00E−05 0.44 0.19 0.33 3.93E−02 1.76 0.26
kgp24415534 2 174156875 ? ? ? 3.40E−05 0.05 0.00 0.05 1.10E−02 0.14 0.00
kgp10594414 1 216039833 USH2A Silent INTRON 3.57E−05 0.05 0.00 0.05 1.25E−02 0.25 0.01
rs10841337 12 19897179 ? ? ? 4.26E−05 0.47 0.22 0.37 4.27E−02 0.64 0.27
rs543122 3 124164156 KALRN, Silent, INTRON 4.73E−05 0.50 0.41 0.57 1.39E−02 0.59 0.44
KA Sile
kgp4705854 12 19907696 ? ? ? 5.01E−05 0.51 0.30 0.47 2.87E−02 0.63 0.33
kgp8192546 12 19903173 ? ? ? 6.52E−05 0.47 0.21 0.36 2.64E−02 0.62 0.26
kgp12008955 2 73759636 ALMS1 Silent INTRON 9.26E−05 ? 0.00 0.04 3.65E−04 0.12 0.01
kgp5564995 6 26414060 BTN3A1, Silent, UTR, 1.56E−04 3.35 0.15 0.06 3.98E−02 2.30 0.14
B Sile EXON
kgp1699628 6 18032535 ? ? ? 1.73E−04 0.51 0.44 0.58 2.99E−02 0.63 0.47
kgp1009249 12 19838534 ? ? ? 1.74E−04 0.48 0.18 0.31 1.03E−02 0.54 0.21
rs9579566 13 30980265 ? ? ? 2.08E−04 0.23 0.02 0.08 9.90E−03 0.30 0.02
kgp26026546 13 79972606 RBM26 Silent INTRON 2.20E−04 ? 0.00 0.03 4.46E−04 0.06 0.00
rs17577980 6 32359821 HCG23 Silent INTRON 2.33E−04 2.36 0.23 0.11 5.31E−03 2.94 0.16
kgp9288015 6 28194629 ZNF193, Silent, INTRON 2.71E−04 0.48 0.14 0.26 3.92E−02 0.61 0.22
ZN Sile
kgp10619195 4 99417717 TSPAN5 Silent INTRON 2.87E−04 0.29 0.04 0.10 3.30E−02 0.46 0.05
kgp6022882 6 28197186 ZNF193, Silent, INTRON 3.03E−04 0.48 0.14 0.26 3.95E−02 0.61 0.22
ZN Sile
rs1579771 3 157278882 C3orf55, Silent, INTRON 3.35E−04 2.02 0.38 0.25 1.64E−02 1.81 0.36
C Sile
kgp8474976 6 32407906 HLA-DRA Silent INTRON 3.66E−04 2.72 0.17 0.08 4.16E−02 2.35 0.12
kgp6127371 4 153856357 ? ? ? 3.69E−04 0.18 0.01 0.06 9.38E−03 0.28 0.02
kgp11210903 22 30898906 SEC14L4, Silent, INTRON 3.70E−04 0.10 0.01 0.05 4.98E−02 0.19 0.00
S Sile
kgp5869992 12 49219569 CACNB3, Silent, INTRON 3.71E−04 0.57 0.39 0.54 2.00E−02 0.62 0.38
C Sile
rs6535882 4 153848128 ? ? ? 3.83E−04 0.18 0.01 0.06 9.06E−03 0.27 0.02
kgp6700691 4 153849531 ? ? ? 3.83E−04 0.18 0.01 0.06 9.06E−03 0.27 0.02
kgp2356388 16 19771577 IQCK Silent INTRON 3.88E−04 0.43 0.12 0.22 1.94E−03 0.45 0.14
kgp3933330 7 28583709 CREB5, Silent, INTRON 4.00E−04 2.42 0.20 0.09 3.21E−02 2.15 0.16
CR Sile
kgp4559907 6 133255252 ? ? ? 4.08E−04 0.56 0.31 0.45 3.11E−02 0.63 0.35
rs10456405 6 32212867 ? ? ? 4.24E−04 1.94 0.33 0.19 4.00E−02 1.80 0.22
kgp4127859 6 32434481 ? ? ? 4.49E−04 2.42 0.20 0.10 1.43E−02 2.53 0.16
rs11022778 11 13390860 ARNTL, Silent, INTRON 4.49E−04 1.96 0.34 0.20 4.87E−02 1.58 0.37
AR Sile
rs1508102 11 116379889 ? ? ? 4.99E−04 0.34 0.04 0.12 4.52E−02 0.50 0.05
kgp4223880 2 10584122 ODC1 Silent INTRON 4.99E−04 0.06 0.00 0.04 3.23E−02 0.22 0.01
kgp9627338 17 90155 RPH3AL, Silent, INTRON 5.01E−04 0.47 0.10 0.21 3.13E−03 0.43 0.11
R Sile
kgp2446153 5 152980439 GRIA, Silent, INTRON 5.31E−04 0.06 0.00 0.04 3.17E−02 0.22 0.01
GR Sile
kgp1786079 7 144701118 ? ? ? 5.35E−04 0.48 0.11 0.21 9.86E−03 0.49 0.13
rs7191155 16 19800213 IQCK Missense EXON 5.38E−04 0.44 0.12 0.22 1.93E−03 0.45 0.14
rs9931167 16 19782598 IQCK Silent INTRON 5.38E−04 0.44 0.12 0.22 1.94E−03 0.45 0.14
rs3829539 16 19722366 C16orf88 Silent INTRON 5.38E−04 0.44 0.12 0.22 2.10E−03 0.45 0.15
kgp1584138 9 124827130 TTLL11, Silent, INTRON 0.000545 0.24 0.02 0.08 3.99E−02 0.45 0.03
TT Sile
b. Additive Model, Genome Wide Analysis, p-value sorted by Combined cohort (GALA, FORTE, and Combined cohorts)
kgp24415534 2 174156875 ? ? ? 3.40E−05 0.05 0.00 0.05 1.10E−02 0.14 0.00
kgp12008955 2 73759636 ALMS1 Silent INTRON 9.26E−05 ? 0.00 0.04 3.65E−04 0.12 0.01
kgp26026546 13 79972606 RBM26 Silent INTRON 2.20E−04 ? 0.00 0.03 4.46E−04 0.06 0.00
rs16886004 7 78021500 MAGI2 Silent INTRON, 2.28E−03 2.15 0.20 0.11 3.25E−05 5.56 0.20
E
kgp25952891 13 80027089 ? ? ? 5.58E−04 ? 0.00 0.03 4.30E−04 0.06 0.00
kgp3450875 16 57268931 RSPRY1 Silent INTRON 6.63E−03 0.19 0.01 0.04 1.51E−05 0.07 0.00
rs10251797 7 78025427 MAGI2 Silent INTRON, 3.18E−03 2.07 0.20 0.11 4.05E−05 5.49 0.19
E
kgp2299675 20 16933074 ? ? ? 4.43E−03 0.26 0.02 0.05 4.23E−05 0.13 0.01
kgp10594414 1 216039833 USH2A Silent INTRON 3.57E−05 0.05 0.00 0.05 1.25E−02 0.24 0.01
kgp1688752 21 43016736 ? ? ? 8.83E−04 0.34 0.05 0.11 1.48E−03 0.33 0.03
kgp12230354 5 27037978 CDH9 Silent INTRON 3.70E−03 0.21 0.01 0.05 3.31E−05 0.14 0.02
rs543122 3 124164156 KALRN, Silent, INTRON 4.73E−05 0.50 0.41 0.57 1.39E−02 0.59 0.44
KA Sile
kgp6236949 2 60301030 ? ? ? 6.37E−04 0.56 0.31 0.44 7.57E−03 0.55 0.26
kgp9627338 17 90155 RPH3AL, Silent, INTRON 5.01E−04 0.47 0.10 0.21 3.13E−03 0.43 0.11
R Sile
kgp11141512 20 35283733 NDRG3, Silent, INTRON 3.33E−03 0.30 0.02 0.07 3.65E−04 0.12 0.01
N Sile
rs9579566 13 30980265 ? ? ? 2.08E−04 0.23 0.02 0.08 9.90E−03 0.30 0.02
rs2816838 10 52714759 ? ? ? 1.94E−03 0.51 0.14 0.23 1.80E−03 0.42 0.11
kgp4705854 12 19907696 ? ? ? 5.01E−05 0.51 0.30 0.47 2.87E−02 0.63 0.33
rs9817308 3 124182136 KALRN, Silent, INTRON 2.85E−05 0.49 0.41 0.58 2.64E−02 0.62 0.45
KA Sile
kgp8817856 6 32744440 ? ? ? 6.02E−04 0.53 0.36 0.49 3.73E−04 0.46 0.42
kgp6214351 11 75546691 UVRAG Silent INTRON 3.98E−03 0.42 0.05 0.11 2.65E−04 0.26 0.04
kgp2356388 16 19771577 IQCK Silent INTRON 3.88E−04 0.43 0.12 0.22 1.94E−03 0.45 0.14
kgp7416024 9 21453902 ? ? ? 2.14E−03 0.13 0.01 0.04 3.81E−04 0.12 0.01
rs6718758 2 60328802 ? ? ? 5.70E−03 0.63 0.33 0.45 5.96E−04 0.47 0.28
rs7579987 2 60307009 ? ? ? 6.99E−03 0.64 0.36 0.47 3.91E−04 0.45 0.31
rs7217872 17 88988 RPH3AL, Silent, INTRON 1.03E−03 0.49 0.11 0.20 2.42E−03 0.42 0.11
R Sile
rs13394010 2 60302746 ? ? ? 7.74E−03 0.64 0.35 0.46 3.91E−04 0.45 0.31
rs7191155 16 19800213 IQCK Missense EXON 5.38E−04 0.44 0.12 0.22 1.93E−03 0.45 0.14
rs9931167 16 19792598 IQCK Silent INTRON 5.38E−04 0.44 0.12 0.22 1.94E−03 0.45 0.14
rs11691553 2 60303554 ? ? ? 8.54E−03 0.65 0.35 0.46 3.72E−04 0.45 0.31
rs11648129 16 19820694 IQCK Silent INTRON 6.54E−04 0.45 0.12 0.22 1.64E−03 0.44 0.14
kgp25216186 1 23758427 ASP3, Silent, INTRON 1.32E−03 0.07 0.00 0.03 2.45E−03 0.07 0.00
AS Sile
kgp29794723 10 18397332 ? ? ? 4.77E−03 0.31 0.02 0.07 3.54E−04 0.18 0.02
rs3829539 16 19722366 C16orf88 Silent INTRON 5.38E−04 0.44 0.12 0.22 2.10E−03 0.45 0.15
rs6895094 5 141037277 ARAP3 Silent INTRON 6.58E−04 0.56 0.38 0.52 1.19E−02 0.60 0.35
kgp1009249 12 19838534 ? ? ? 1.74E−04 0.48 0.18 0.31 1.03E−02 0.54 0.21
rs10203396 2 60305100 ? ? ? 8.67E−03 0.65 0.36 0.46 4.43E−04 0.46 0.31
kgp3854180 16 19721806 C16orf88 Silent INTRON 6.54E−04 0.45 0.12 0.22 1.94E−03 0.45 0.14
rs6497396 16 19735697 IQCK Silent INTRON 1.30E−03 0.48 0.13 0.23 7.65E−04 0.43 0.16
rs8055485 16 19750051 IQCK Silent INTRON 6.54E−04 0.45 0.12 0.22 2.10E−03 0.45 0.15
rs9931211 16 19813605 IQCK Silent INTRON 6.54E−04 0.45 0.12 0.22 2.10E−03 0.45 0.15
FORTE COMBINED
Al- Re- Al-
lele gres- Al- lele
Freq. sion lele Freq. DD Dd dd
(Con- Armi- Odds Freq. (Con- DD (Con- Dd (Con- dd (Con-
Name trol tage Ratio (Case trols) (Cases) trol (Cases) trol (Cases) trol
Additive Model, Genome Wide Analysis, p-value sorted by GALA cohort (GALA, FORTE, and Combined cohorts)
kgp541056 0.16 4.67E−02 0.75 0.22 0.27 15 15 146 69 238 97
rs9817308 0.57 5.18E−06 0.55 0.43 0.57 71 55 199 96 127 29
rs1749972 0.17 4.33E−02 0.74 0.22 0.28 15 15 146 68 237 95
kgp24415534 0.03 3.98E−07 0.08 0.00 0.04 0 0 3 16 396 165
kgp10594414 0.05 2.44E−06 0.14 0.01 0.05 0 0 6 18 391 163
rs10841337 0.36 1.56E−05 0.55 0.24 0.36 22 24 147 84 227 73
rs543122 0.57 3.17E−06 0.54 0.42 0.57 70 54 195 97 131 29
kgp4705854 0.43 4.80E−06 0.55 0.31 0.46 41 38 169 89 189 54
kgp8192546 0.36 1.29E−05 0.55 0.24 0.36 21 23 146 84 232 74
kgp12008955 0.06 3.98E−07 0.08 0.00 0.04 0 0 3 16 396 165
kgp5564995 0.07 2.28E−05 2.88 0.14 0.06 1 0 109 21 274 151
kgp1699628 0.58 2.72E−05 0.57 0.45 0.58 72 52 218 85 109 32
kgp1009249 0.32 9.55E−06 0.51 0.20 0.31 10 16 136 80 253 84
rs9579566 0.07 4.19E−06 0.26 0.02 0.08 0 1 18 27 381 153
kgp26026546 0.04 4.46E−07 0.03 0.00 0.04 0 0 1 13 397 167
rs17577980 0.07 1.66E−05 2.36 0.20 0.09 13 5 130 23 255 150
kgp9288015 0.30 1.76E−04 0.57 0.18 0.28 13 11 117 78 267 92
kgp10619195 0.10 3.54E−05 0.36 0.04 0.10 0 2 32 33 366 146
kgp6022882 0.30 1.99E−04 0.57 0.18 0.28 13 11 118 78 267 92
rs1579771 0.25 1.96E−05 1.91 0.37 0.25 39 9 213 71 146 101
kgp8474976 0.06 1.64E−04 2.39 0.15 0.07 3 0 111 26 285 155
kgp6127371 0.07 1.23E−05 0.23 0.02 0.06 0 0 13 23 384 157
kgp11210903 0.02 1.48E−05 0.12 0.01 0.04 0 0 4 14 395 167
kgp5869992 0.50 1.13E−05 0.58 0.38 0.53 60 58 184 74 152 48
rs6535882 0.07 1.24E−05 0.23 0.02 0.06 0 0 13 23 386 158
kgp6700691 0.07 1.24E−05 0.23 0.02 0.06 0 0 13 23 386 158
kgp2356388 0.26 5.78E−06 0.46 0.13 0.23 4 5 98 75 297 101
kgp3933330 0.08 6.67E−05 2.26 0.18 0.09 15 1 111 29 271 151
kgp4559907 0.46 6.02E−05 0.60 0.33 0.46 46 37 171 91 180 53
rs10456405 0.13 2.89E−04 1.75 0.27 0.17 35 11 144 38 212 129
kgp4127859 0.07 5.43E−05 2.32 0.18 0.09 8 0 127 33 263 148
rs11022778 0.27 2.37E−05 1.86 0.35 0.23 52 5 176 72 171 104
rs1508102 0.11 9.87E−05 0.42 0.05 0.12 0 4 41 34 357 143
kgp4223880 0.03 4.19E−05 0.13 0.01 0.04 0 0 4 13 394 167
kgp9627338 0.20 3.52E−06 0.45 0.10 0.21 6 7 71 61 320 113
kgp2446153 0.03 4.35E−05 0.13 0.01 0.04 0 0 4 13 395 168
kgp1786079 0.22 2.09E−05 0.49 0.12 0.22 4 11 86 56 308 114
rs7191155 0.26 7.89E−06 0.46 0.13 0.23 4 5 97 74 295 101
rs9931167 0.26 8.07E−06 0.46 0.13 0.23 4 5 98 74 297 101
rs3829539 0.26 8.80E−06 0.47 0.13 0.23 4 5 98 74 296 101
kgp1584138 0.08 1.47E−04 0.35 0.03 0.08 1 1 20 26 378 154
b. Additive Model, Genome Wide Analysis, p-value sorted by Combined cohort (GALA, FORTE, and Combined cohorts)
kgp24415534 0.03 3.98E−07 0.08 0.00 0.04 0 0 3 16 396 165
kgp12008955 0.06 3.98E−07 0.08 0.00 0.04 0 0 3 16 396 165
kgp26026546 0.04 4.46E−07 0.03 0.00 0.04 0 0 1 13 397 167
rs16886004 0.05 9.81E−07 2.79 0.20 0.09 6 2 147 28 246 149
kgp25952891 0.04 1.41E−06 0.04 0.00 0.03 0 0 1 12 398 168
kgp3450875 0.07 1.99E−06 0.12 0.01 0.05 0 0 5 17 394 164
rs10251797 0.05 2.21E−06 2.67 0.20 0.09 6 2 145 29 248 150
kgp2299675 0.08 2.28E−06 0.19 0.01 0.06 0 0 11 23 388 158
kgp10594414 0.05 2.44E−06 0.14 0.01 0.05 0 0 6 18 391 163
kgp1688752 0.11 2.53E−06 0.33 0.04 0.11 1 2 30 37 368 142
kgp12230354 0.09 2.74E−06 0.19 0.01 0.06 0 0 10 22 386 159
rs543122 0.57 3.17E−06 0.54 0.42 0.57 70 54 195 97 131 29
kgp6236949 0.39 3.26E−06 0.54 0.28 0.42 30 34 166 85 203 62
kgp9627338 0.20 3.52E−06 0.45 0.10 0.21 6 7 71 61 320 113
kgp11141512 0.06 4.12E−06 0.21 0.01 0.06 0 1 11 21 388 158
rs9579566 0.07 4.19E−06 0.26 0.02 0.08 0 1 18 27 381 153
rs2816838 0.22 4.79E−06 0.46 0.13 0.23 4 8 92 67 303 106
kgp4705854 0.43 4.80E−06 0.55 0.31 0.46 41 38 169 89 189 54
rs9817308 0.57 5.18E−06 0.55 0.43 0.57 71 55 199 96 127 29
kgp8817856 0.60 5.33E−06 0.53 0.39 0.53 50 44 208 103 135 34
kgp6214351 0.13 5.51E−06 0.35 0.05 0.12 0 2 37 39 361 140
kgp2356388 0.26 5.78E−06 0.46 0.13 0.23 4 5 98 75 297 101
kgp7416024 0.06 6.06E−06 0.13 0.01 0.04 0 0 5 16 393 165
rs6718758 0.44 6.08E−06 0.55 0.31 0.44 35 38 175 85 189 58
rs7579987 0.48 6.43E−06 0.55 0.33 0.47 40 41 184 87 175 52
rs7217872 0.21 7.50E−06 0.47 0.11 0.21 6 7 74 61 319 113
rs13394010 0.48 7.81E−06 0.56 0.33 0.47 39 41 185 86 175 53
rs7191155 0.26 7.89E−06 0.46 0.13 0.23 4 5 97 74 295 101
rs9931167 0.26 8.07E−06 0.46 0.13 0.23 4 5 98 74 297 101
rs11691553 0.48 8.19E−06 0.56 0.33 0.47 39 41 183 86 174 53
rs11648129 0.26 8.23E−06 0.47 0.13 0.23 4 5 97 74 297 102
kgp25216186 0.03 8.36E−06 0.07 0.00 0.03 0 0 2 12 397 169
kgp29794723 0.08 8.64E−06 0.25 0.02 0.07 0 0 16 26 382 155
rs3829539 0.26 8.80E−06 0.47 0.13 0.23 4 5 98 74 296 101
rs6895094 0.48 9.24E−06 0.57 0.37 0.51 56 46 181 92 161 43
kgp1009249 0.32 9.55E−06 0.51 0.20 0.31 10 16 136 80 253 84
rs10203396 0.48 9.72E−06 0.56 0.33 0.47 39 41 186 87 173 53
kgp3854180 0.26 1.00E−05 0.47 0.13 0.23 4 5 98 74 297 102
rs6497396 0.29 1.02E−05 0.48 0.14 0.25 6 6 102 77 290 98
rs8055485 0.26 1.09E−05 0.47 0.13 0.23 4 5 98 74 296 102
rs9931211 0.26 1.09E−05 0.47 0.13 0.23 4 5 98 74 296 102
indicates data missing or illegible when filed
TABLE 9
GALA FORTE Combined
Odds Odds Odds
Gene Ratio Ratio Ratio
Loca- (Minor (Minor (Minor DD Dd dd
tions Fisher's Al- Fisher's Al- Fisher's Al- DD (Con- Dd (Con- dd (Con-
Name Chr Positio Gene Mutati (s) Exact lele) Exact lele) Exact lele) (Cases) trol (Cases) trol (Cases) trol
Allelic Model, Genome Wide Analysis, p-value sorted by GALA cohort (GALA, FORTE, and Combined cohorts)
rs9817308 3 1.24E+08 KALRN, Silent, INTRON 3.87E−05 0.50 3.01E−02 0.63 8.10E−06 0.56 71 55 199 96 127 29
K Sil
kgp4705854 12 19907696 ? ? ? 4.32E−05 0.50 3.06E−02 0.63 4.85E−06 0.55 41 38 169 89 189 54
kgp24415534 2 1.74E+08 ? ? ? 6.03E−05 0.05 2.85E−02 0.15 2.28E−06 0.08 0 0 3 16 396 165
kgp10594414 1 2.16E+08 USH2A Silent INTRON 6.25E−05 0.05 2.37E−02 0.24 1.11E−05 0.15 0 0 6 18 391 163
rs543122 3 1.24E+08 KALRN, Silent, INTRON 7.67E−05 0.51 1.70E−02 0.60 4.37E−06 0.55 70 54 195 97 131 29
K Sil
kgp8192546 12 19903173 ? ? ? 1.01E−04 0.49 2.88E−02 0.61 1.91E−05 0.55 21 23 146 84 232 74
rs17577980 6 32359821 HCG23 Silent INTRON 1.11E−04 2.50 6.83E−03 2.75 6.67E−06 2.39 13 5 130 23 255 150
kgp12008955 2 73759636 ALMS1 Silent INTRON 1.41E−04 0.00 2.03E−03 0.12 2.28E−06 0.08 0 0 3 16 396 165
rs10456405 6 32212867 ? ? ? 1.42E−04 2.11 3.72E−02 1.85 9.81E−05 1.86 35 11 144 38 212 129
kgp22779568 X 23029377 ? ? ? 1.52E−04 0.42 4.82E−02 0.58 3.73E−05 0.50 16 21 68 39 313 121
kgp2784875 10 1.25E+08 ? ? ? 1.55E−04 2.07 4.05E−02 1.64 1.52E−05 1.90 94 20 90 40 174 100
kgp22730987 X 68448739 ? ? ? 1.75E−04 2.65 4.14E−02 2.06 1.50E−05 2.39 30 3 79 24 280 153
kgp3933330 7 28583709 CREB5, Silent, INTRON 1.76E−04 2.57 3.68E−02 2.09 2.62E−05 2.31 15 1 111 29 271 151
CR Sil
kgp20478926 8 21050249 ? ? ? 1.80E−04 0.23 5.60E−04 0.25 6.56E−07 0.26 5 15 14 8 377 156
kgp5869992 12 49219569 CACNB3, Silent, INTRON 2.02E−04 0.54 2.03E−02 0.61 6.60E−06 0.56 60 58 184 74 152 48
Sil
rs9579566 13 30980265 ? ? ? 2.52E−04 0.23 2.24E−02 0.32 1.45E−05 0.26 0 1 18 27 381 153
kgp8372688 6 32212264 ? ? ? 2.65E−04 1.93 3.97E−02 1.67 9.53E−05 1.75 51 15 175 55 171 111
kgp1009249 12 19838534 ? ? ? 2.79E−04 0.49 2.04E−02 0.57 2.35E−05 0.54 10 16 136 80 253 84
kgp1786079 7 1.45E+08 ? ? ? 3.11E−04 0.44 2.02E−02 0.53 2.57E−05 0.49 4 11 86 56 308 114
kgp3919159 6 32379506 ? ? ? 3.46E−04 2.25 2.31E−02 2.29 1.06E−04 2.08 13 5 127 27 255 147
kgp4559907 6 1.33E+08 ? ? ? 3.48E−04 0.54 4.22E−02 0.64 6.01E−05 0.59 46 37 171 91 180 53
kgp2626546 13 79972606 RBM26 Silent INTRON 3.66E−04 0.00 3.19E−03 0.06 2.24E−06 0.03 0 0 1 13 397 167
kgp30662075 X 1.14E+08 HTR2C, Silent, INTRON, 3.92E−04 0.00 9.14E−03 0.21 6.62E−05 0.15 0 3 5 9 391 169
H Sil E
kgp22793211 X 92601576 ? ? ? 3.96E−04 0.55 3.25E−03 0.54 3.81E−06 0.55 93 65 126 65 177 50
kgp1699628 6 18032535 ? ? ? 3.96E−04 0.55 3.84E−02 0.64 4.60E−05 0.59 72 62 218 85 109 32
kgp9627338 17 90155 RPH3AL Silent, INTRON 4.17E−04 0.44 5.38E−03 0.46 5.09E−06 0.45 6 7 71 61 320 113
Sil
rs7228827 18 76900411 ATP9B Silent INTRON 5.41E−04 2.25 2.10E−02 2.06 2.89E−05 2.15 20 1 124 37 254 143
rs6618396 X 89549121 ? ? ? 5.45E−04 0.41 4.87E−02 0.46 1.30E−05 0.39 8 13 32 25 357 143
kgp4127859 6 32434481 ? ? ? 5.88E−Q4 2.31 2.31E−02 2.30 6.64E−05 2.18 8 0 127 33 263 148
kgp6236949 2 60301030 ? ? ? 6.28E−04 0.56 1.19E−02 0.56 4.07E−06 0.54 30 34 166 85 203 62
rs5952097 X 1.16E+08 ? ? ? 6.33E−04 0.40 1.19E−02 0.48 7.78E−05 0.47 13 11 43 39 343 131
rs1508102 11 1.16E+08 ? ? ? 6.75E−04 0.34 4.77E−02 0.49 1.85E−04 0.41 0 4 41 34 357 143
kgp6127371 4 1.54E+08 ? ? ? 7.09E−04 0.19 1.67E−02 0.29 6.10E−05 0.24 0 0 13 23 384 157
rs6535882 4 1.54E+08 ? ? ? 7.25E−04 0.19 1.63E−02 0.29 6.13E−05 0.24 0 0 13 23 386 158
kgp6700691 4 1.54E+08 ? ? ? 7.25E−04 0.19 1.63E−02 0.29 6.13E−05 0.24 0 0 13 23 386 158
rs4326550 X 92580637 ? ? ? 7.32E−04 0.57 1.57E−02 0.60 2.43E−05 0.58 96 64 127 64 176 52
kgp4418535 6 32431558 ? ? ? 8.39E−04 2.28 3.24E−02 2.25 1.24E−04 2.14 8 0 125 33 266 148
kgp10372946 10 1.34E+08 JAKMIP3 Silent INTRON 8.73E−04 12.71 2.35E−02 7.01 1.79E−05 10.00 0 0 42 2 357 179
rs1579771 3 1.57E+08 C3orf55, Silent, INTRON 8.82E−04 1.85 2.77E−02 1.69 5.03E−05 1.77 39 9 213 71 146 101
Sil
kgp11804835 6 32396146 ? ? ? 8.96E−04 2.33 1.39E−02 2.51 5.98E−05 2.27 8 1 119 28 270 152
kgp3812034 2 43427044 ? ? ? 9.06E−04 0.54 2.95E−02 0.61 9.65E−05 0.58 28 26 137 78 226 76
b. Allelic Model, Genome Wide Analysis, p-value sorted by Combined cohort (GALA, FORTE, and Combined cohorts)
kgp20478926 8 21050249 ? ? ? 1.80E−04 0.23 5.60E−04 0.25 6.56E−07 0.26 5 15 14 8 377 156
rs16886004 7 78021500 MAGI2 Silent INTRON, 3.92E−03 2.01 3.71E−05 4.80 1.41E−06 2.53 6 2 147 28 246 149
E
kgp26026546 13 79972606 RBM26 Silent INTRON 3.66E−04 0.00 3.19E−03 0.06 2.24E−06 0.03 0 0 1 13 397 167
kgp24415534 2 1.74E+08 ? ? ? 6.03E−05 0.05 2.85E−02 0.15 2.28E−06 0.08 0 0 3 16 396 165
kgp12008955 2 73759636 ALMS1 Silent INTRON 1.41E−04 0.00 2.03E−03 0.12 2.28E−06 0.08 0 0 3 16 396 165
kgp12125601 5 1.52E+08 ? ? ? 2.80E−03 1.77 3.73E−03 1.92 2.86E−06 1.95 136 35 35 17 219 122
rs10251797 7 78025427 MAGI2 Silent INTRON, 4.27E−03 1.97 5.87E−05 4.65 3.32E−06 2.44 6 2 145 29 248 150
E
kgp22793211 X 92601576 ? ? ? 3.96E−04 0.55 3.25E−03 0.54 3.81E−06 0.55 93 65 126 65 177 50
kgp6236949 2 60301030 ? ? ? 6.28E−04 0.56 1.19E−02 0.56 4.07E−06 0.54 30 34 166 85 203 62
rs543122 3 1.24E+08 KALRN, Silent, INTRON 7.67E−05 0.51 1.70E−02 0.60 4.37E−06 0.55 70 54 195 97 131 29
K Sil
kgp24743841 1 63899572 ALG6 Silent INTRON 9.49E−04 2.85 6.85E−03 2.70 4.63E−06 2.88 48 8 20 4 326 165
kgp4705854 12 19907696 ? ? ? 4.32E−05 0.50 3.06E−02 0.63 4.85E−06 0.55 41 38 169 89 189 54
kgp9627338 17 90155 RPH3AL, Silent, INTRON 4.17E−04 0.44 5.38E−03 0.46 5.09E−06 0.45 6 7 71 61 320 113
Sil
kgp1688752 21 43016736 ? ? ? 2.14E−03 0.38 1.85E−03 0.28 5.78E−06 0.33 1 2 30 37 368 142
kgp5869992 12 49219569 CACNB3, Silent, INTRON 2.02E−04 0.54 2.03E−02 0.61 6.60E−06 0.56 60 58 184 74 152 48
Sil
rs17577980 6 32359821 HCG23 Silent INTRON 1.11E−04 2.50 6.83E−03 2.75 6.67E−06 2.39 13 5 130 23 255 150
kgp25952891 13 80027089 ? ? ? 9.94E−04 0.00 3.13E−03 0.06 6.71E−06 0.04 0 0 1 12 398 168
kgp8110667 22 32716792 ? ? ? 4.71E−03 ? 6.16E−03 ? 7.05E−06 ? 1 0 30 0 367 181
kgp11210241 3 38537237 ? ? ? 2.62E−03 ? 1.03E−02 ? 7.12E−06 ? 1 0 30 0 368 181
rs17687961 22 32716927 ? ? ? 4.71E−03 ? 6.20E−03 ? 7.12E−06 ? 1 0 30 0 368 181
rs12013377 X 92620062 ? ? ? 1.35E−03 0.59 2.51E−03 0.53 7.90E−06 0.56 97 66 129 66 173 49
rs7579987 2 60307009 ? ? ? 7.27E−03 0.63 7.35E−04 0.49 7.90E−06 0.56 40 41 184 87 175 52
rs6718758 2 60328802 ? ? ? 5.30E−03 0.62 1.23E−03 0.49 8.06E−06 0.55 35 38 175 85 189 58
rs9817308 3 1.24E+08 KALRN, Silent, INTRON 3.87E−05 0.50 3.01E−02 0.63 8.10E−06 0.56 71 55 199 95 127 29
Sil
kgp22804809 X 92585610 ? ? ? 1.10E−02 1.54 5.12E−05 2.39 8.38E−06 1.79 139 38 132 59 127 84
rs6895094 5 1.41E+08 ARAP3 Silent INTRON 9.49E−04 0.57 1.07E−02 0.58 8.54E−06 0.56 56 46 181 92 161 43
kgp3450875 16 57268931 RSPRY1 Silent INTRON 1.25E−02 0.20 2.10E−04 0.07 9.56E−06 0.13 0 0 5 17 394 164
rs11691553 2 60303554 ? ? ? 9.11E−03 0.64 7.16E−04 0.48 1.02E−05 0.56 39 41 183 86 174 53
rs13394010 2 60302746 ? ? ? 7.30E−03 0.64 7.35E−04 0.49 1.04E−05 0.56 39 41 185 86 175 53
rs2139612 X 92614918 ? ? ? 1.79E−03 0.59 3.37E−03 0.54 1.04E−05 0.57 96 65 129 67 173 49
kgp11328629 10 1.21E+08 ? ? ? 3.11E−03 2.49 1.97E−03 3.81 1.10E−05 2.86 6 0 97 19 295 162
kgp10594414 1 2.16E+08 USH2A Silent INTRON 6.25E−05 0.05 2.37E−02 0.24 1.11E−05 0.15 0 0 6 18 391 163
kgp11141512 20 35283733 NDRG3, Silent, INTRON 4.28E−03 0.29 2.03E−03 0.12 1.19E−05 0.20 0 1 11 21 388 158
Sil
rs2816838 10 52714759 ? ? ? 3.47E−03 0.53 3.94E−03 0.44 1.23E−05 0.48 4 8 92 67 303 106
kgp2299675 20 16933074 ? ? ? 7.25E−03 0.27 3.48E−04 0.14 1.24E−05 0.21 0 0 11 23 388 158
rs6618396 X 89549121 ? ? ? 5.45E−04 0.41 4.87E−02 0.46 1.30E−05 0.39 8 13 32 25 357 143
rs7217872 17 88988 RPH3AL, Silent, INTRON 9.84E−04 0.46 5.73E−03 0.45 1.39E−05 0.46 6 7 74 61 319 113
Sil
rs9579566 13 30980265 ? ? ? 2.52E−04 0.23 2.24E−02 0.32 1.45E−05 0.26 0 1 18 27 381 153
rs10203396 2 60305110 ? ? ? 9.47E−03 0.64 1.05E−03 0.49 1.46E−05 0.57 39 41 186 87 173 53
rs13419758 2 60302920 ? ? ? 9.47E−03 0.64 1.07E−03 0.49 1.48E−05 0.57 40 41 185 87 174 53
kgp22730987 X 68448739 ? ? ? 1.75E−04 2.65 4.14E−02 2.06 1.50E−05 2.39 30 3 79 24 280 153
kgp9320791 2 60309952 ? ? ? 9.47E−03 0.64 1.09E−03 0.50 1.52E−05 0.57 39 41 187 87 172 53
kgp2784875 10 1.25E+08 ? ? ? 1.55E−04 2.07 4.05E−02 1.64 1.52E−05 1.90 94 20 90 40 174 100
kgp6507761 7 319681 ? ? ? 8.80E−03 0.64 1.70E−03 0.51 1.53E−05 0.57 78 61 185 83 135 37
kgp6214351 11 75546691 UVRAG Silent INTRON 4.74E−03 0.42 1.08E−03 0.29 1.60E−05 0.36 0 2 37 39 361 140
kgp12230354 5 2703797 CDH9 Silent INTRON 5.97E−03 0.21 2.69E−04 0.15 1.65E−05 0.20 0 0 10 22 386 159
indicates data missing or illegible when filed
In some embodiments genetic markers presented in Tables 8-9 are identified as predictive of response to glatiramer acetate if the p-value for the Combined cohort is less than about 0.05, less than about 0.01, less than about 0.005, less than about 0.001, or less than about 0.0005, less than about 10−4, less than about 5*10−5, less than about 10−5, less than about 5*10−6, less than about 10−6 or less than about 5*10−7.
In the fourth stage of the analysis, the placebo cohort (n=196: 95 R vs. 101 NR) (GALA placebo) was analyzed to identify variants associated with placebo response/non-response. These results will be used to confirm whether significantly associated variants are specific to glatiramer acetate drug response versus disease severity.
Overlap with Placebo Cohort Results:
An analysis to investigate whether any of the highly associated variants (P<0.0001) from the combined cohorts in the additive association analysis showed a similar significant association in the placebo cohort was conducted. This analysis identified two overlapping associations with the placebo associations, which include the 132nd top associated variant in the combined cohorts (variant kpg5144181) and the 242nd top associated variant in the combined cohort (kpg7063887).
Results for Standard Response Definition, Placebo Cohort Results for Additive and Allelic models are presented in tables 10-11, respectively.
TABLE 10
Additive Model, Genome Wide Placebo Cohort Analysis
GALA PLACEBO cohort
Al-
Gene Regres- Al- lele
Loca- Armi- sion lele Freq. DD Dd dd
Posi- Muta- tions tage Odds Freq. (Con- DD (Con- Dd (Con- dd (Con-
Name Chr tion Gene(s) tion (s) P Ratio (Cases) trols) (Cases) trols) (Cases) trols) (Cases) trols)
rs12472695 2 65804266 ? ? ? 2.31E−05 0.38 31% 51% 10 21 39 62 46 18
kgp3188 2 65804244 ? ? ? 2.99E−05 0.39 36% 56% 13 25 41 63 40 13
kgp5747456 2 23932556 ? ? ? 3.24E−05 Infinity 8% 0% 0 0 15 0 80 101
rs11562998 2 51814215 ? ? ? 3.41E−05 6.52 14% 2% 2 0 23 5 70 96
rs11563025 2 51864372 ? ? ? 3.41E−05 6.52 14% 2% 2 0 23 5 70 96
rs16846161 2 2.12E+08 ERBB4, ER Silent, INTRON 3.72E−05 12.04 12% 1% 2 0 18 2 74 97
Sile
kgp22839559 ? ? ? 3.97E−05 2.82 34% 16% 10 2 44 28 40 70
kgp12562255 1 2.01E+08 ? ? ? 4.21E−05 21.79 9% 0% 0 0 17 1 78 100
kgp6990559 1 7014101 CAMTA1 Silent INTRON, E 4.49E−05 0.44 35% 58% 15 35 36 42 43 20
rs6577395 1 6991925 CAMTA1 Silent INTRON, E 5.34E−05 0.45 37% 59% 16 38 37 43 41 20
kgp4456934 2 2.18E+08 DIRC3 Silent INTRON 5.68E−05 3.79 21% 7% 4 0 31 13 60 87
rs10495115 1 2.19E+08 ? ? ? 6.04E−05 2.90 30% 13% 7 2 43 23 45 76
kgp4137144 1 2.19E+08 ? ? ? 6.13E−05 6.19 14% 3% 2 0 22 5 70 95
rs3768769 2 1.14E+08 IL36A Silent INTRON 7.21E−05 4.30 17% 5% 2 0 29 10 64 91
kgp3488270 1 20335423 ? ? ? 7.30E−05 0.27 6% 21% 1 4 10 33 84 63
rs2354380 2 51826155 ? ? ? 7.48E−05 5.49 14% 3% 2 0 23 6 69 95
kgp7151153 3 79590648 ROBO1 Silent INTRON 7.86E−05 3.98 18% 5% 4 1 27 8 64 92
rs28993969 2 1.14E+08 ? ? ? 8.51E−05 3.67 20% 6% 4 0 30 13 61 88
rs12043743 1 1.97E+08 KCNT2 Silent INTRON 8.61E−05 0.16 3% 13% 0 0 5 26 90 75
kgp24521552 2 1.44E+08 ARHGAP1 Silent INTRON 8.86E−05 4.22 17% 5% 4 0 25 9 66 91
kgp11755256 2 42245135 ? ? ? 8.99E−05 0.38 14% 32% 1 14 25 37 68 50
rs528065 2 23859449 KLHL29 Silent INTRON 9.24E−05 2.45 44% 26% 19 3 46 46 30 52
rs13386874 2 51820543 ? ? ? 9.25E−05 2.64 32% 15% 12 1 37 28 46 72
kgp956070 2 2.06E+08 PARD3B, P Silent, INTRON 9.39E−05 0.37 14% 32% 2 11 23 41 70 48
Sile
rs35615951 2 1.34E+08 NCKAP5, N Silent, INTRON 9.41E−05 2.32 48% 28% 22 8 46 41 26 52
Sile
kgp12253568 3 79428265 ROBO1 Silent INTRON 9.55E−05 4.29 17% 4% 4 1 24 6 67 94
rs1397481 2 2.06E+08 PARD3B, P Silent, INTRON 9.56E−05 0.37 14% 31% 2 10 23 43 70 48
Sile
kgp7161038 2 53521025 ? ? ? 9.70E−05 0.09 1% 10% 0 0 2 20 92 81
rs1534647 2 62038088 ? ? ? 9.72E−05 3.34 22% 8% 5 0 32 16 58 85
kgp7799142 3 13902000 WNT7A Silent INTRON 1.04E−04 0.12 2% 11% 0 0 3 22 91 79
kgp6029 2 1.69E+08 ? ? ? 1.07E−04 0.37 13% 30% 2 11 21 39 72 51
kgp8142606 2 1.74E+08 ? ? ? 1.10E−04 0.22 4% 17% 0 3 8 27 87 70
rs6737616 2 51807660 ? ? ? 1.18E−04 5.98 13% 2% 1 0 22 5 72 96
kgp7713264 2 2.42E+08 GPR35, GP Silent, INTRON 1.18E−04 0.45 30% 51% 10 27 37 47 47 26
Sile
kgp8055964 3 1.73E+08 SPATA16 Silent INTRON 1.19E−04 Infinity 7% 0% 0 0 13 0 82 101
rs12712821 2 42238864 ? ? ? 1.19E−04 0.39 15% 32% 1 14 26 37 68 50
rs13424176 2 42239532 ? ? ? 1.19E−04 0.39 15% 32% 1 14 26 37 68 50
kgp9777128 2 42242872 ? ? ? 1.19E−04 0.39 15% 32% 1 14 26 37 68 50
rs10195970 2 42249643 ? ? ? 1.19E−04 0.39 15% 32% 1 14 26 37 68 50
rs10177811 2 42263580 ? ? ? 1.19E−04 0.39 15% 32% 1 14 26 37 68 50
indicates data missing or illegible when filed
TABLE 11
Allelic Model, Genome Wide Placebo Cohort Analysis
GALA PLACEBO cohort
Al-
Gene Al- lele
Chro- Loca- Fisher's lele Freq. DD Dd dd
mo- Posi- Muta- tions Exact Freq. (Con- DD (Con- Dd (Con- dd (Con-
Name some tion Gene(s) tion (s) P (Cases) trols) (Cases) trols) (Cases) trols) (Cases) trols)
kgp54189 5 73992881 HEXB Mis- EXON 8.76E−07 9% 25% 3 3 11 44 81 54
sense
kgp34948 14 91731724 ? ? ? 1.53E−06 6% 17% 3 1 5 32 87 67
kgp21160 14 91744233 CCOC88C Silent INTRON 1.55E−06 6% 17% 3 1 5 32 86 67
kgp28774 6 1644677 GMDS, Silent, INTRON 2.43E−06 14% 2% 0 0 27 4 68 97
GM Sil
rs1175074 5 73973220 ? ? ? 2.71E−06 9% 25% 3 4 11 42 81 55
rsl223398 5 73975094 ? ? ? 2.71E−06 9% 25% 3 4 11 42 81 55
rs1203094 1 67701765 IL23R Silent INTRON 3.44E−06 36% 37% 20 5 29 64 46 32
rs3894712 5 73973651 ? ? ? 3.50E−05 9% 25% 3 5 11 41 81 55
rs3858038 9 2988280 ? ? ? 4.13E−06 53% 30% 33 7 34 46 28 48
kgp62594 5 73973306 ? ? ? 5.26E−06 9% 24% 3 4 11 41 81 56
rs7159692 14 91729406 ? ? ? 6.22E−06 7% 18% 3 1 7 34 85 66
kgp43335 8 41496314 ? ? ? 7.73E−06 23% 46% 6 19 32 55 57 27
kgp60425 3 1.94E+08 LOC10050 Silent INTRON 8.38E−06 1% 12% 0 1 2 22 93 77
kgp89109 8 4818950 CSMD1 Silent INTRON 8.91E−06 45% 33% 27 5 32 57 36 39
kgp48182 14 86277089 ? ? ? 8.95E−06 45% 36% 10 18 66 36 19 47
kgp66017 19 28886975 ? ? ? 9.85E−06 19% 31% 7 3 21 55 65 42
kgp574745 2 23932556 ? ? ? 1.03E−05 8% 0% 0 0 15 0 80 101
kgp64292 15 62931802 MGC1588 Silent INTRON 1.03E−05 8% 0% 0 0 15 0 80 101
kgp82762 14 91725476 ? ? ? 1.22E−05 7% 17% 3 1 7 33 85 67
kgp68282 9 8373943 PTPRD, Silent, INTRON 1.23E−05 26% 10% 3 2 43 17 48 82
PT Sil
rs3847233 9 2987835 ? ? ? 1.32E−05 52% 30% 31 7 34 46 28 47
kgp3188 2 65804244 ? ? ? 1.34E−05 36% 56% 13 25 41 63 40 13
rs1890118 6 82857479 ? ? ? 1.48E−05 26% 32% 13 4 23 56 59 41
rs2282624 11 57001911 APLNR, Silent, INTRON, 1.54E−05 30% 35% 15 5 27 61 53 35
AP Sil E
kgp48924 9 2995617 ? ? ? 1.54E−05 52% 30% 31 7 36 47 28 47
kgp11285 9 2953403 ? ? ? 1.66E−05 46% 23% 26 5 35 37 34 59
rs4740708 9 2993975 ? ? ? 1.67E−05 51% 30% 31 7 34 47 29 47
rs695915 1 82664165 ? ? ? 1.90E−05 34% 28% 6 17 51 23 37 61
rs2327006 6 1.31E+08 EPB41L2, Silent, INTRON 1.93E−05 22% 9% 1 2 39 13 55 84
Sil
kgp93349 6 1.31E+08 EPB41L2, Silent, INTRON 2.05E−05 22% 8% 2 2 38 13 55 86
Sil
rs193933 19 8331375 ? ? ? 2.07E−05 27% 46% 11 17 30 59 54 25
kgp12475 4 1.86E+08 ACSL1 Silent INTRON 2.11E−05 13% 3% 0 1 24 4 71 96
rs1247269 2 65804266 ? ? ? 2.11E−05 31% 51% 10 21 39 62 46 18
rs1393040 9 2985743 ? ? ? 2.31E−05 48% 27% 28 6 35 42 31 53
kgp29209 17 39694480 ? ? ? 2.33E−05 10% 27% 0 6 19 43 76 52
rs209568 8 17612639 MTUS1, Synonym EXON 2.34E−05 27% 11% 4 0 44 22 47 79
M
kgp12562 1 2.01E+08 ? ? ? 2.42E−05 9% 0% 0 0 17 1 78 100
kgp26263 13 67483846 PCDH9, Silent, INTRON, 2.43E−05 34% 49% 4 28 56 43 34 30
P Sil E
kgp16821 5 2047397 ? ? ? 2.51E−05 1% 10% 0 1 1 18 94 82
kgp10148 4 89767803 FAM13A Silent INTRON 2.55E−05 15% 2% 3 0 23 5 68 96
kgp57600 6 1.31E+08 EPB41L2, Silent, INTRON 2.61E−05 20% 7% 1 2 35 11 58 88
Sil
kgp78398 1 95321361 SLC44A3, Silent, INTRON 2.67E−05 20% 20% 0 11 38 19 57 71
S Sil
rs1049917 6 1.31E+08 EPB41L2, Silent, INTRON 2.77E−05 19% 7% 1 2 35 11 59 88
Sil
kgp37781 19 28893126 ? ? ? 2.80E−05 19% 32% 7 4 23 56 65 41
kgp76534 17 39694186 ? ? ? 2.81E−05 10% 27% 0 5 19 44 76 52
rs1684616 2 2.12E+08 ERBB4, Silent, INTRON 2.96E−05 12% 1% 2 0 18 2 74 97
ER Sil
indicates data missing or illegible when filed
Example 9 Analysis for Extreme Responders Vs. Extreme Non-Responders Part 1—Analysis of Candidate Variants The initial analysis was analyzed to 35 genetic variants in high priority genes. Power (80%) with Bonferroni statistical correction for multiple testing to identify significant genetic associations with an odds ratio >4, for variants with an allele frequency greater than 10%.
Results for Extreme Response Definition, Candidate Variants Selected a priori for Additive and Allelic models are presented in tables 12-13, respectively.
In some embodiments genetic markers presented in Tables 12-13 are identified as predictive of response to glatiramer acetate if the p-value for the GALA cohort is less than about 0.15, less than about 0.13, less than about 0.07 or less than about 0.06.
In some embodiments genetic markers presented in Tables 12-1.3 are identified as predictive of response to glatiramer acetate if the p-value for the FORTE cohort is less than about 0.10, less than about 0.05, less than about 0.01, less than about 0.005 or less than about 0.001.
In some embodiments genetic markers presented in Tables 12-13 are identified as predictive of response to glatiramer acetate if the p-value for the Combined cohort is less than about 0.10, less than about 0.05, less than about 0.01, less than about 0.005 or less than about 0.001.
TABLE 12
Additive Model, Extreme Response Definition, Candidate Variants (GALA, FORTE, and Combined cohorts)
GALA FORTE COMBINED
Al- Al- Al-
Armi- Al- lele Armi- Al- lele Armi- Al- lele
tage lele Freq. tage lele Freq. tage lele Freq.
P- Odds Freq. (Non- P- Odds Freq. (Non- P- Odds Freq. (Non-
Source Name Ch Gene value Ratio (Resp.) Resp.) value Ratio (Resp.) Resp.) valu Ratio (Resp.) Resp.)
Tchelet GWAS rs3135391 6 HLA-DRB1 0.060 0.58 18% 27% 0.028 0.50 20% 33% 0.0064 0.57 19% 29%
Tchelet GWAS rs3135388 6 HLA-DRB1 0.069 0.59 18% 27% 0.028 0.50 20% 33% 0.0075 0.58 19% 29%
Tchelet GWAS rs2487896 10 HPSE2 0.130 0.60 11% 17% 0.0017 0.33 12% 29% 0.0044 0.51 11% 20%
Tchelet GWAS rs108536 18 MEX3C 0.149 0.70 36% 44% 0.56 1.18 43% 39% 0.54 0.90 40% 43%
Tchelet GWAS rs109880 9 SET 0.231 0.48 3% 6% 0.0010 0.18 3% 14% 0.0051 0.33 3% 8%
Comi rs269976 18 SLC14A2 0.288 1.62 8% 5% 0.28 2.33 6% 3% 0.21 1.61 7% 5%
Tsareva 2011 rs231775 2 CTLA4 0.318 1.28 43% 38% 0.46 1.22 37% 31% 0.39 1.16 40% 36%
Grossman 2007 rs946685 1 IL12RB2 0.342 1.32 21% 17% 0.84 0.92 15% 16% 0.75 1.08 18% 17%
Tsareva 2011 rs1800629 6 TNF 0.355 0.74 13% 17% 0.86 1.07 12% 11% 0.39 0.82 13% 15%
Tchelet GWAS rs1007328 15 AC012409.1 0.364 1.24 57% 52% 0.051 0.57 45% 59% 0.38 0.86 50% 54%
Tchelet GWAS rs1225688 10 CYP26C1 0.366 0.79 30% 34% 0.23 1.46 35% 27% 0.93 1.02 33% 32%
Tchelet GWAS rs1093109 2 AC074182.1 0.387 1.38 11% 8% 0.42 0.69 7% 10% 0.96 1.01 8% 8%
Tchelet GWAS rs4148871 6 TAP2 0.421 0.79 17% 20% 0.98 1.01 23% 23% 0.83 0.95 20% 21%
Tchelet GWAS rs947603 10 CEP55 0.436 1.26 23% 19% 0.033 2.30 24% 11% 0.06 1.51 24% 17%
Grossman 2007 rs2001791 3 CD86 0.439 1.29 16% 13% 0.32 0.71 15% 20% 0.93 1.02 15% 15%
Tsareva 2011 rs6897932 5 IL7Ra 0.493 0.84 21% 24% 0.84 1.07 24% 23% 0.77 0.94 23% 24%
Comi rs1558896 7 TAC1 0.506 1.17 33% 30% 0.27 0.71 26% 33% 0.70 0.93 29% 31%
Grossman 2007 rs1415148 1 CTSS 0.555 0.86 36% 40% 0.39 1.28 42% 36% 0.79 1.05 40% 38%
Tchelet GWAS rs1777193 8 AC016885.1 0.555 1.17 28% 25% 0.000020 0.27 24% 53% 0.067 0.71 26% 33%
Grossman 2007 rs2275235 1 CTSS 0.634 0.88 32% 34% 0.16 1.52 40% 30% 0.41 1.16 36% 33%
Tchelet GWAS rs1573706 20 PTPRT 0.638 0.87 18% 20% 0.00048 0.28 11% 29% 0.0071 0.55 14% 23%
Tchelet GWAS rs1159962 10 RP11-655H13.1 0.653 0.84 11% 12% 0.98 1.01 10% 10% 0.64 0.88 10% 12%
Comi rs974060 7 TAC1 0.654 1.12 30% 28% 0.19 0.67 25% 33% 0.57 0.90 27% 29%
Comi rs4890535 18 SLC14A2 0.656 1.19 9% 8% 0.64 1.28 9% 7% 0.52 1.21 9% 7%
Tchelet GWAS rs1757545 2 AC078940.2 0.664 0.89 30% 33% 0.018 0.52 30% 47% 0.11 0.75 30% 37%
Tchelet GWAS rs2521644 7 NPY 0.679 1.11 45% 42% 0.83 1.06 44% 43% 0.64 1.09 45% 43%
Grossman 2007 rs1129055 3 CD86 0.775 1.08 26% 24% 0.19 0.68 30% 39% 0.91 0.98 28% 29%
Tchelet GWAS rs4343256 15 CRTC3 0.808 1.14 5% 5% 0.044 0.37 6% 13% 0.42 0.75 5% 7%
Tchelet GWAS rs6097801 20 CYP24A1 0.823 0.93 14% 15% 0.0057 0.41 9% 24% 0.043 0.63 11% 17%
Tchelet GWAS rs2177073 18 DTNA 0.864 0.94 12% 13% 0.10 0.51 10% 17% 0.23 0.74 11% 14%
Tchelet GWAS rs1095035 7 AC074389.1 0.866 0.96 33% 34% 0.15 1.62 29% 20% 0.85 1.04 31% 30%
Tchelet GWAS rs4369324 10 RP11-655H13.2 0.920 1.03 22% 22% 0.35 1.42 20% 14% 0.72 1.08 21% 19%
Tchelet GWAS rs1161713 3 RP11-629E24.2 0.959 0.98 7% 7% 0.0022 0.14 2% 10% 0.052 0.49 4% 8%
Tchelet GWAS rs4344916 2 AC083939.1 0.962 1.01 31% 31% 0.08 0.63 26% 39% 0.24 0.81 28% 33%
Tchelet GWAS rs9944913 18 NOL4 0.981 1.01 13% 13% 0.36 0.66 9% 13% 0.42 0.80 11% 13%
indicates data missing or illegible when filed
TABLE 13
Allelic Model, Extreme Response Definition, Candidate Variants (GALA, FORTE, and Combined cohorts)
GALA FORTE
Odds Al- Odds Al-
Ratio Al- lele Ratio Al- lele
Fisher's (Minor lele Freq. Fisher's (Minor lele Freq.
Posi- Exact Al- Freq. (Con- Exact Al- Freq. (Con-
Source Name Ch tion Gene P lele) (Cases) trols) P lele) (Cases) trols)
Tchelet rs3135388 6 32413051 HLA-DRB1 0.075234 0.599034 0.181818 0.270588 0.031164 0.500152 0.196629 0.328571
GWAS
Tchelet rs3135391 6 32410987 HLA-DRB1 0.075291 0.591017 0.181818 0.273256 0.031164 0.500152 0.196629 0.328571
GWAS
Tchelet rs2487896 10 1.01E+08 HPSE2 0.135493 0.576856 0.106061 0.170588 0.002228 0.334395 0.117978 0.285714
GWAS
Tchelet rs1085360 18 48783342 MEX3C 0.195547 0.721805 0.363636 0.44186 0.570435 1.186638 0.426966 0.385714
GWAS
Tchelet rs1098808 9 1.31E+08 SET 0.281834 0.5 0.030303 0.058824 0.001601 0.17341 0.02809 0.142857
GWAS
Tsareva rs231775 2 2.05E+08 CTLA4 0.347935 1.251077 0.431818 0.377907 0.452026 1.285714 0.370787 0.314286
2011
Comi rs269976 18 42781787 SLC14A2 0.351837 1.646465 0.083333 0.052326 0.361681 2.239521 0.061798 0.028571
Grossman rs946685 1 67815715 IL12RB2 0.374886 1.327586 0.212121 0.168605 0.845141 0.929697 0.147727 0.157143
2007
Tchelet rs1225688 10 94827183 CYP26C1 0.38939 0.803171 0.295455 0.343023 0.29301 1.434664 0.348315 0.271429
GWAS
Tchelet rs1007328 15 96703373 AC012409.1 0.417114 1.227085 0.568182 0.517442 0.066407 0.577402 0.449438 0.585714
GWAS
Tchelet rs1093109 2 1.85E+08 AC074182.1 0.417558 1.451108 0.106061 0.075581 0.428339 0.650602 0.067416 0.1
Tsareva rs1800629 6 31543031 TNF 0.419818 0.728936 0.128788 0.168605 1 1.092949 0.123596 0.114286
2011
Tchelet rs4148871 6 32803316 TAP2 0.46037 0.782857 0.166667 0.203488 1 1.010036 0.230337 0.228571
GWAS
Tchelet rs947603 10 95249605 CEP55 0.477454 1.238859 0.227273 0.19186 0.023852 2.505639 0.244318 0.114286
GWAS
Grossman rs2001791 3 1.22E+08 CD86 0.507354 1.289926 0.159091 0.127907 0.33832 0.684211 0.146067 0.2
2007
Comi rs1558896 7 97281912 TAC1 0.533334 1.186275 0.333333 0.296512 0.274375 0.712121 0.258427 0.328571
Tsareva rs6897932 5 35874575 1L7Ra 0.582979 0.833333 0.212121 0.244186 0.870005 1.075 0.241573 0.228571
2011
Tchelet rs1777193 8 94259105 AC016885.1 0.5999 1.168421 0.280303 0.25 2.18E−05 0.284084 0.241573 0.528571
GWAS
Grossman rs1415148 1 1.51E+08 CTSS 0.634082 0.87395 0.363636 0.395349 0.3899 1.30099 0.41954 0.357143
2007
Tchelet rs1573706 20 40921149 PTPRT 0.66336 0.869841 0.181818 0.203488 0.000892 0.298742 0.106742 0.285714
GWAS
Comi rs4890535 18 42760370 SLC14A2 0.676761 1.223077 0.090909 0.075581 0.801757 1.283951 0.089888 0.071429
Comi rs974060 7 97271508 TAC1 0.702366 1.123188 0.30303 0.27907 0.206336 0.670993 0.247191 0.328571
Tchelet rs1757545 2 76624220 AC078940.2 0.70994 0.900621 0.30303 0.325581 0.017315 0.483124 0.301136 0.471429
GWAS
Grossman rs2275235 1 1.51E+08 CTSS 0.712828 0.893785 0.318182 0.343023 0.187836 1.540881 0.397727 0.3
2007
Tchelet rs1159962 10 1.11E+08 RP11- 0.719551 0.853107 0.106061 0.122093 1 1.0125 0.101124 0.1
GWAS 655H13.1
Tchelet rs2521644 7 24427969 NPY 0.726947 1.096078 0.44697 0.424419 0.887361 1.063973 0.44382 0.428571
GWAS
Grossman rs1129055 3 1.22E+08 CD86 0.79101 1.073858 0.257576 0.244186 0.227117 0.675259 0.297753 0.385714
2007
Tchelet rs6097801 20 52767434 CYP24A1 0.869321 0.928421 0.136364 0.145349 0.002983 0.307916 0.089888 0.242857
GWAS
Tchelet rs1095035 7 1800967 AC074389.1 0.903004 0.957627 0.333333 0.343023 0.153622 1.650794 0.292135 0.2
GWAS
Tchelet rs1161713 13 30590793 RP11- 1 0.97561 0.068182 0.069767 0.006286 0.154286 0.016854 0.1
GWAS 629E24.2
Tchelet rs2177073 18 32054724 DTNA 1 0.940439 0.121212 0.127907 0.122899 0.510352 0.095506 0.171429
GWAS
Tchelet rs4343256 15 91198415 CRTC3 1 1.134 0.05303 0.047059 0.065025 0.403439 0.05618 0.128571
GWAS
Tchelet rs4344916 2 35597319 AC083939.1 1 1.011611 0.310606 0.36814 0.063797 0.563533 0.261364 0.385714
GWAS
Tchelet rs4369324 10 1.11E+08 RP11- 1 1.027289 0.219697 0.215116 0.364915 1.468531 0.196626 0.142857
GWAS 655H13.2
Tchelet rs9944913 18 31926438 NOL4 1 1.007905 0.128788 0.127907 0.357373 0.66941 0.089888 0.128571
GWAS
COMBINED
Odds Al-
Ratio Al- lele
Fisher's (Minor lele Freq. DD Dd dd
Exact Al- Freq. (Con- DD (Con- Dd (Con- dd (Con-
Source P lele) (Cases) trols) (Cases) trols) (Cases) trols) (Cases) trols)
Tchelet 0.008221 0.582539 0.190323 0.2875 6 9 47 51 102 60
GWAS
Tchelet 0.008266 0.577575 0.190323 0.289256 6 9 47 52 102 60
GWAS
Tchelet 0.003985 0.496104 0.112903 0.204167 3 6 29 37 123 77
GWAS
Tchelet 0.601035 0.899676 0.4 0.42562 28 17 68 69 59 35
GWAS
Tchelet 0.006355 0.328904 0.029032 0.083333 0 1 9 18 146 101
GWAS
Tsareva 0.378507 1.171861 0.396774 0.359504 26 18 71 51 58 52
2011
Comi 0.277651 1.604167 0.070968 0.045455 0 1 22 9 133 111
Grossman 0.819741 1.073622 0.175325 0.165289 5 2 44 36 105 83
2007
Tchelet 1 1.016072 0.325806 0.322314 15 11 71 56 69 54
GWAS
Tchelet 0.392171 0.861538 0.5 0.53719 39 32 77 66 39 23
GWAS
Tchelet 1 1.016197 0.083871 0.082645 2 3 22 14 131 104
Tsareva 0.384855 0.797347 0.125806 0.152893 6 4 27 29 122 88
2011
Tchelet 0.832981 0.955227 0.203226 0.210744 4 7 55 37 96 77
GWAS
Tchelet 0.056786 1.522885 0.237013 0.169421 7 6 59 29 88 86
GWAS
Grossman 1 1.022602 0.151613 0.14876 6 2 35 32 114 87
2007
Comi 0.708106 0.928747 0.290323 0.305785 18 9 54 56 83 56
Tsareva 0.83943 0.942433 0.229032 0.239669 8 7 55 44 92 70
2011
Tchelet 0.072395 0.704348 0.258065 0.330579 9 16 62 48 84 57
GWAS
Grossman 0.860062 1.047893 0.395425 0.384298 25 16 71 61 57 44
2007
Tchelet 0.009585 0.547566 0.13871 0.227273 2 7 39 41 114 73
GWAS
Comi 0.53794 1.235619 0.090323 0.07438 1 3 26 12 128 106
Comi 0.568262 0.895176 0.270968 0.293388 14 9 56 53 85 59
Tchelet 0.120633 0.743611 0.301948 0.367769 15 17 63 55 76 49
GWAS
Grossman 0.471074 1.157143 0.363636 0.330579 21 11 70 58 63 52
2007
Tchelet 0.680358 0.879753 0.103226 0.115702 2 1 28 26 125 94
GWAS
Tchelet 0.666085 1.08275 0.445161 0.42562 28 22 82 59 45 40
GWAS
Grossman 0.924318 0.978163 0.280645 0.285124 12 8 63 53 80 60
2007
Tchelet 0.034456 0.586611 0.109677 0.173554 7 3 20 36 128 82
GWAS
Tchelet 0.852865 1.038535 0.309677 0.301653 21 10 54 53 80 58
GWAS
Tchelet 0.061019 0.472625 0.03871 0.078512 1 1 10 17 144 103
GWAS
Tchelet 0.238954 0.728817 0.106452 0.140496 2 3 29 28 124 90
GWAS
Tchelet 0.477974 0.761092 0.054839 0.070833 0 0 17 17 138 103
GWAS
Tchelet 0.226351 0.797172 0.282468 0.330579 19 11 49 58 86 52
GWAS
Tchelet 0.749071 1.079398 0.206452 0.194215 6 5 52 37 97 79
GWAS
Tchelet 0.503205 0.810877 0.106452 0.128099 0 2 33 27 122 92
GWAS
indicates data missing or illegible when filed
Example 10 Analysis for Extreme Responders Vs. Extreme Non-Responders Part 2—Analysis of Candidate Genes (30) The second analysis was analyzed to a selected set of genetic variants in 30 priority candidate genes (4,012 variants). Power (80%) to identify significant genetic associations with an odds ratio >7, for variants with an allele frequency greater than 10%.
Results for Extreme Response Definition, Analysis of Candidate Genes (30) Selected a priori for Additive and Allelic models are presented in tables 14-15, respectively. No variants replicated in both cohorts (P<0.05). Less stringent (P<0.10+P<0.05) values were used.
In some embodiments genetic markers presented in Tables 14-15 are identified as predictive of response to glatiramer acetate if the p-value for the GALA cohort is less than about 0.10, less than about 0.09, less than about 0.08, less than about 0.07 or less than about 0.02.
In some embodiments genetic markers presented in Tables 14-15 are identified as predictive of response to glatiramer acetate if the p-value for the FORTE cohort is less than about 0.05, less than about 0.02, less than about 0.01 or less than about 0.005.
In some embodiments genetic markers presented in Tables 14-15 are identified as predictive of response to glatiramer acetate if the p-value for the Combined cohort is less than about 0.05, less than about 0.01 or less than about 0.005.
TABLE 14
Additive Model, Extreme Response Definition Analysis of Candidate Genes (30) (GALA, FORTE, and Combined cohorts)
GALA FORTE COMBINED
Regres- Regres- Regres-
Armi- sion Armi- sion Armi- sion DD Dd dd
tage Odds tage Odds tage Odds DD (Con- Dd (Con- dd (Con-
Columns Gene Chr P Ratio P Ratio P Ratio (Cas trol (Cas trol (Cas trol
rs1894408 HLA-DOB/ 6 0.089 1.50 0.003 2.85 0.0012 1.86 22 10 81 47 50 64
TAP2
rs1894407 HLA-DOB/ 6 0.082 1.52 0.008 2.50 0.0024 1.78 21 10 82 48 51 63
TAP2
rs1894406 HLA-DOB/ 6 0.072 1.54 0.009 2.52 0.0037 1.74 20 9 78 46 57 66
TAP2
rs12454490 SLC14A2 18 0.082 1.88 0.033 3.66 0.0119 2.10 2 1 40 16 113 104
indicates data missing or illegible when filed
TABLE 15
Allelic Model, Extreme Response Definition, Analysis of Candidate Genes (30) (GALA, FORTE, and Combined cohorts)
GALA FORTE
Odds Ratio Allele Allele Odds Ratio Allele Allele
Posi- Fisher's (Minor Freq. Freq. Fisher's (Minor Freq. Freq.
Column Chr tion Exact Allele (Case (Controls) Exact Allele (Case (Controls)
rs1894406 6 32787056 0.066 1.58 39% 28% 0.016 2.21 38% 21%
rs17884784 4 123541500 0.082 4.05 5% 1% 0.024 0.09 1% 6%
rs1894408 6 32785833 0.087 1.53 39% 30% 0.005 2.45 42% 23%
rs1834407 6 32787036 0.087 1.54 39% 30% 0.018 2.16 41% 24%
COMBINED
Odds Ratio Allele Allele DD Dd dd
Fisher's (Minor Freq. Freq. DD (Con- Dd (Con- dd (Con-
Column Exact Allele (Case (Controls) (Cases) trols (Cases) trols (Cases) trols
rs1894406 0.005 1.71 38% 26% 20 9 78 46 57 66
rs17884784 1.000 0.91 2% 2% 0 0 7 6 147 115
rs1894408 0.002 1.80 42% 28% 22 10 81 47 50 64
rs1834407 0.003 1.72 40% 28% 21 10 82 48 51 63
Example 11 Analysis for Extreme Responders Vs. Extreme Non-Responders Part 3—Analysis of Candidate Genes (180) The third analysis was analyzed to a selected set of genetic variants in 180 priority candidate genes (25,461 variants). Power (80%) to identify significant genetic associations with an odds ratio >7, for variants with an allele frequency greater than 10%.
Results for Extreme Response Definition, Analysis of Candidate Genes (180) Selected a priori for Additive and Allelic models are presented in tables 16-17, respectively.
In some embodiments genetic markers presented in Tables 16-17 are identified as predictive of response to glatiramer acetate if the p-value for the GALA cohort is less than about 0.05, less than about 0.01, less than about 0.005, less than about 0.001, less than about 0.0005 or less than about 10′4.
In some embodiments genetic markers presented in Tables 16-17 are identified as predictive of response to glatiramer acetate if the p-value for the FORTE cohort is less than about 0.05, less than about 0.01, less than about 0.005 or less than about 0.001.
In some embodiments genetic markers presented in Tables 16-17 are identified as predictive of response to glatiramer acetate if the p-value for the Combined cohort is less than about 0.05, less than about 0.01, less than about 0.005, less than about 0.001, less than about 0.0005 or less than about 10−4.
TABLE 16
Additive Model, Extreme Response Definition Analysis of Candidate Genes (180) (GALA, FORTE, and Combined cohorts)
GALA FORTE COMBINED
Al- Al- Al-
Armi- Al- lele Armi- Al- lele Armi- Al- lele
tage lele Freq. tage lele Freq. tage lele Freq. DD Dd dd
Func- P- Odds Freq. (Non- P-- Odds Freq. (Non- P-- Odds Freq. (Non- DD (Con- Dd (Con- dd (Con-
Names Ch Gene tio valu Rat (Resp Resp valu Ratio (Resp Resp valu Ratio (Resp Resp (Cases trol (Cases trol (Cases trol
rs6110157 20 MACROD2 intron 0.022 0.53 22% 33% 0.0078 0.45 18% 34% 0.00018 0.47 81% 67% 6 13 47 55 100 53
kgp401177 10 HPSE2 intron 0.025 0.25 2% 8% 0.023 ? 0% 3% 0.00025 0.13 99% 93% 0 0 3 16 151 105
kgp3496814 13 ALOX5AP intron 0.029 0.60 39% 52% 0.00086 0.37 43% 67% 0.00061 0.55 58% 43% 28 39 73 59 54 23
rs10162089 13 ALOX5AP intron 0.006 1.93 56% 40% 0.0053 2.32 46% 26% 0.00094 1.78 50% 64% 43 14 69 57 42 48
rs3885907 13 ALOX5AP intron 0.016 1.73 52% 38% 0.0027 2.56 46% 24% 0.00097 1.77 52% 66% 41 13 68 56 46 52
rs17238927 13 ALOX5AP intron 0.042 0.15 1% 5% 0.023 ? 0% 3% 0.0013 0.07 100% 96% 0 0 1 10 154 110
rs9671124 13 ALOX5AP intran 0.022 1.69 56% 42% 0.0020 2.57 49% 27% 0.0013 1.74 48% 62% 46 17 70 58 39 46
rs4769060 13 ALOX5AP intron 0.030 1.69 50% 38% 0.0037 2.43 47% 26% 0.0013 1.77 52% 66% 38 12 73 59 44 50
rs4075692 13 ALOX5AP intron 0.022 1.69 56% 42% 0.0023 2.55 49% 27% 0.0016 1.72 48% 62% 45 17 71 58 39 46
rs11147439 13 ALOX5AP intron 0.018 0.57 36% 50% 0.0089 0.48 42% 61% 0.0019 0.59 60% 47% 28 33 67 63 60 25
kgp3776689 10 HPSE2 intron 0.044 1.90 19% 11% 0.036 2.48 21% 10% 0.0020 2.16 80% 90% 9 0 45 25 100 95
kgp304921 20 MACROD2 intron 0.042 0.34 3% 10% 0.027 0.29 3% 10% 0.0021 0.32 97% 90% 1 2 7 19 144 98
rs3803277 13 ALOX5AP intron 0.016 0.57 37% 51% 0.012 0.49 43% 61% 0.0021 0.59 59% 46% 28 35 70 61 57 25
kgp5440506 13 ALOX5AP intron 0.017 0.57 36% 50% 0.011 0.49 43% 62% 0.0025 0.60 60% 47% 29 33 65 62 60 25
rs9671182 13 ALOX5AP intron 0.019 0.57 37% 51% 0.014 0.50 43% 61% 0.0028 0.60 59% 46% 29 33 68 63 58 24
rs4254166 13 ALOX5AP intron 0.025 0.59 37% 50% 0.011 0.49 43% 61% 0.0029 0.60 50% 47% 28 33 69 63 58 25
rs4356336 13 ALOX5AP intron 0.020 0.58 37% 51% 0.014 0.50 43% 61% 0.0029 0.60 59% 46% 29 34 68 62 58 25
rs11002051 10 KCNMA1 intron 0.015 0.29 4% 11% 0.028 0.38 7% 16% 0.0031 0.39 95% 88% 0 1 17 28 138 92
rs10278591 7 MAD1L1 intron 0.016 1.95 30% 19% 0.043 2.15 26% 14% 0.0032 1.88 72% 83% 13 2 61 38 81 81
rs4360791 13 ALOX5AP intron 0.018 0.57 38% 52% 0.021 0.53 44% 61% 0.0034 0.61 58% 45% 30 36 69 60 56 25
kgp2715873 13 ALOX5AP intron 0.025 0.59 37% 50% 0.014 0.50 43% 61% 0.0038 0.61 59% 47% 29 33 68 63 58 25
rs9315047 13 ALOX5AP intron 0.025 0.59 37% 50% 0.014 0.50 43% 61% 0.0038 0.61 59% 47% 29 33 68 63 58 25
rs9670531 13 ALOX5AP intron 0.025 0.59 37% 50% 0.014 0.50 43% 61% 0.0038 0.61 59% 47% 29 33 68 63 58 25
rs4584668 13 ALOX5AP intron 0.026 0.59 37% 50% 0.014 0.50 43% 61% 0.0039 0.61 59% 47% 29 33 68 62 58 25
rs9508832 13 ALOX5AP intron 0.022 1.73 49% 36% 0.011 2.21 41% 23% 0.0043 1.65 55% 68% 35 11 68 56 52 54
kgp7117398 7 MAD1L1 intron 0.023 1.88 30% 19% 0.043 2.15 26% 14% 0.0045 1.83 72% 82% 13 2 61 39 81 80
kgp4370912 10 KCNMA1 intron 0.032 0.33 4% 10% 0.028 0.38 7% 16% 0.0074 0.42 95% 88% 0 1 17 26 138 93
TABLE 17
Allelic Model, Extreme Response Definition, Analysis of Candidate Genes (180) (GALA, FORTE, and Combined cohorts)
GALA FORTE COMBINED
Odds Al- Odds Al- Odds Al-
Ratio Al- lele Ratio Al- lele Ratio Al- lele
Fisher's (Minor lele Freq. Fisher's (Minor lele Freq. Fisher's (Minor lele Freq. DD Dd dd
Posi- Exact Al- Freq. (Con- Exact Al- Freq. (Con- Exact Al- Freq. (Con- DD (Con- Dd (Con- dd (Con-
Columns Chr tion P lele) (Cases) tro P lele) (Cases) trols) P lele) (Cases) tro (Cases) trols (Cases) trols (Cases) trols
rs6110157 20 14055947 0.0285 0.55 22% 33% 0.006 0.41 18% 34% 0.00018 0.47 19% 33% 6 13 47 55 100 53
rs9341808 6 80953257 0.0260 2.11 23% 13% 0.003 4.34 24% 7% 0.00037 2.49 24% 11% 26 9 13 6 99 94
kgp3496814 13 31336379 0.0279 0.59 39% 52% 0.001 0.37 43% 67% 0.00058 0.55 42% 57% 28 39 73 59 54 23
rs3885907 13 31314455 0.0143 1.80 52% 38% 0.002 2.60 46% 24% 0.00070 1.83 48% 34% 41 13 68 56 46 52
rs10162089 13 31316738 0.0073 1.92 56% 40% 0.004 2.46 46% 26% 0.00070 1.82 50% 36% 43 14 69 57 42 48
rs9671124 13 31324253 0.0208 1.73 56% 42% 0.002 2.62 49% 27% 0.00106 1.78 52% 38% 46 17 70 58 39 46
rs4769060 13 31337877 0.0360 1.65 50% 38% 0.003 2.52 47% 26% 0.00130 1.77 48% 34% 38 12 73 59 44 50
rs4075692 13 31323342 0.0208 1.73 56% 42% 0.003 2.57 48% 27% 0.00143 1.76 52% 38% 45 17 71 58 39 46
kgp304921 20 14017077 0.0351 0.31 3% 10% 0.042 0.26 3% 10% 0.00145 0.29 3% 10% 1 2 7 19 144 98
rs11147439 13 31325643 0.0199 0.57 36% 50% 0.007 0.45 42% 61% 0.00148 0.58 40% 53% 28 33 67 63 60 25
kgp3276689 10 100396003 0.0453 2.01 19% 11% 0.044 2.44 21% 10% 0.00150 2.21 20% 10% 9 0 45 25 100 95
kgp5440506 13 31320543 0.0193 0.57 36% 50% 0.010 0.46 43% 62% 0.00190 0.58 40% 53% 29 33 65 62 60 25
rs3803277 13 31318308 0.0199 0.56 37% 51% 0.011 0.49 43% 61% 0.00195 0.58 41% 54% 28 35 70 61 57 25
rs9671182 13 31321138 0.0203 0.58 37% 51% 0.011 0.48 43% 61% 0.00255 0.59 41% 54% 29 33 68 63 58 24
rs4356336 13 31319546 0.0204 0.58 37% 51% 0.011 0.48 43% 61% 0.00260 0.59 41% 54% 29 34 68 62 58 25
rs4254166 13 31322949 0.0273 0.59 37% 50% 0.011 0.47 43% 61% 0.00261 0.59 40% 53% 28 33 69 63 58 25
rs4360791 13 31318020 0.0201 0.57 38% 52% 0.017 0.50 44% 61% 0.00268 0.59 42% 55% 30 36 69 60 56 25
rs10278591 7 1921362 0.0207 1.90 30% 19% 0.045 2.15 26% 14% 0.00329 1.86 28% 17% 13 2 61 38 81 81
rs4584668 13 31319553 0.0271 0.59 37% 50% 0.011 0.48 43% 61% 0.00339 0.60 41% 53% 23 33 68 62 58 25
kgp2715873 13 31320249 0.0273 0.59 37% 50% 0.011 0.48 43% 61% 0.00345 0.60 41% 53% 29 33 68 63 58 25
rs9670531 13 31321069 0.0273 0.59 37% 50% 0.011 0.48 43% 61% 0.00345 0.60 41% 53% 29 33 68 63 58 25
rs9315047 13 31321289 0.0273 0.59 37% 50% 0.011 0.48 43% 61% 0.00345 0.60 41% 53% 29 33 68 63 58 25
rs9508832 13 31314264 0.0257 1.72 49% 36% 0.008 2.35 41% 23% 0.00372 1.69 45% 32% 35 11 68 56 52 54
kgp7117398 7 1915282 0.0301 1.83 30% 19% 0.045 2.15 26% 14% 0.00471 1.81 28% 18% 13 2 61 39 81 80
rs11002051 10 78921392 0.0300 0.32 4% 11% 0.048 0.39 7% 16% 0.00526 0.41 5% 12% 0 1 17 28 138 92
kgp4370912 10 78918287 0.0452 0.35 4% 10% 0.048 0.39 7% 16% 0.01151 0.44 5% 12% 0 1 17 26 138 93
Example 12 Analysis for Extreme Responders Vs. Extreme Non-Responders Part 4—Genome Wide Analysis A full genome-wide analysis (4 M variants) was then conducted. Power (80%) with Bonferroni statistical correction to identify significant genetic associations with an odds ratio >11, for variants with an allele frequency greater than 10%. Approximately 4200 variants were selected for analysis in stage 2 (replication) (P<0.001).
Results for Extreme Response Definition, Genome Wide Analysis for Additive and Allelic models are presented in tables 18-19, respectively.
In some embodiments genetic markers presented in Tables 18-19 are identified as predictive of response to glatiramer acetate if the p-value for the GALA cohort is less than about 0.05, less than about 0.01, less than about 0.001, less than about 0.0005, less than about 10−4 or less than about 5*10−5.
In some embodiments genetic markers presented in Tables 18-19 are identified as predictive of response to glatiramer acetate if the p-value for the FORTE cohort is less than about 0.05, less than about 0.01, less than about 0.001, less than about 0.0005, less than about 10−4 or less than about 5*10−5.
In some embodiments genetic markers presented in Tables 18-19 are identified as predictive of response to glatiramer acetate if the p-value for the Combined cohort is less than about 10−4, less than about 5*10−5, less than about 10−5, less than about 5*10−6, less than about 10−6 or less than about 5*10−7.
Stage 4.
Placebo Cohort (n=102: 23 R vs. 79 NR)—The placebo cohort (GALA placebo) was analyzed to identify variants associated with placebo response/non-response.
Results for Standard Response Definition, Placebo Cohort Results for Additive and Allelic models are presented in tables 20-21, respectively.
TABLE 18
Additive Model, Extreme Response Definition, Genome Wide Analysis (GALA, FORTE, and Combined cohorts)
GALA FORTE
Al- Al-
Armi- Al- lele Armi- Al- lele
tage lele Freq. tage lele Freq.
Loca- P- Odds Freq. (Non- P- Odds Freq. (Non-
Name C Gene tion valu Ratio (Resp Resp valu Rati (Resp Resp
kgp6214351 11 UVRAG INTRON 2.4E−03 0.20 3% 13% 3.4E−05 0.12 3% 17%
rs10026108 4 ? ? 5.5E−05 3.06 62% 41% 8.3E−03 0.42 44% 61%
kgp3984567 4 ? ? 9.8E−05 0.34 38% 59% 6.9E−03 0.42 44% 61%
kgp10948564 20 ? ? 3.4E−03 0.41 20% 33% 4.4E−03 0.41 15% 31%
kgp9627338 17 RPH3AL INTRON 2.5E−03 0.36 8% 22% 2.3E−04 0.23 11% 29%
kgp10788130 12 GRIN2B INTRON 3.6E−03 ? 0% 7% 1.5E−04 0.08 1% 11%
kgp7077322 4 41334 INTRON 1.8E−03 0.13 2% 10% 3.6E−04 0.16 3% 16%
rs7348267 20 ? ? 3.4E−03 0.41 20% 33% 8.9E−03 0.44 15% 38%
rs6032205 20 ? ? 4.4E−03 0.41 20% 34% 1.0E−02 0.44 15% 30%
kgp11768533 11 ? ? 1.1E−03 2.52 50% 34% 1.8E−03 2.75 47% 26%
rs502330 6 ? ? 2.1E−02 0.19 2% 7% 6.2E−05 ? 0% 9%
rs1478682 11 ? ? 7.5E−04 2.57 48% 31% 2.9E−03 2.60 45% 24%
kgp11467007 5 STC2 INTRON 1.5E−03 0.17 2% 13% 1.2E−03 0.22 5% 17%
rs196295 10 BAG3 EXON 3.6E−04 0.35 11% 30% 6.1E−03 0.41 18% 34%
(Synon)
rs196343 10 BAG3 INTRON 4.4E−04 0.36 11% 30% 5.3E−03 0.40 18% 34%
rs7217872 17 RPH3AL, INTRON 3.7E−03 0.37 8% 22% 3.3E−04 0.24 11% 29%
RPH3A
rs1079303 11 ? ? 1.1E−03 2.52 50% 34% 2.3E−03 2.66 47% 26%
rs10501082 11 ? ? 1.1E−03 2.52 50% 34% 2.3E−03 2.66 47% 26%
rs6718758 2 ? ? 6.9E−03 0.53 31% 47% 9.2E−03 0.44 25% 41%
rs7948420 11 ? ? 6.0E−05 0.33 20% 42% 7.0E−03 0.46 33% 51%
kgp18432055 9 TMEM38B UTR 5.2E−04 3.51 20% 6% 8.3E−03 4.81 16% 4%
rs10954782 8 ? ? 3.1E−02 1.66 52% 39% 2.1E−03 0.40 37% 59%
kgp9078300 2 KLHL29 INTRON 1.8E−02 2.18 21% 11% 1.0E−03 4.88 25% 7%
rs7928078 11 ? ? 1.8E−03 2.44 49% 34% 2.3E−03 2.66 47% 26%
kgp9884626 2 ? ? 4.2E−03 ? 0% 6% 5.4E−03 ? 0% 4%
rs9579566 13 ? ? 1.4E−03 ? 0% 8% 7.8E−03 0.17 2% 9%
COMBINED
Al-
Armi- Al- lele
tage lele Freq. DD Dd dd
P- Odds Freq. (Non- DD (Con- Dd (Con- dd (Con-
Name value Rati (Resp Resp (Cases trols) (Cases trols) (Cases trols)
kgp6214351 9.1E−07 0.17 3% 14% 0 1 9 32 145 88
rs10026108 3.2E−06 0.39 42% 60% 21 36 87 72 47 12
kgp3984567 4.4E−06 0.40 41% 60% 21 36 86 72 48 13
kgp10948564 6.4E−06 0.37 17% 33% 4 8 44 63 107 50
kgp9627338 8.2E−06 0.34 10% 24% 1 7 28 44 125 70
kgp10788130 9.7E−06 0.07 1% 8% 0 1 2 18 153 102
kgp7077322 1.0E−05 0.18 3% 12% 0 0 8 28 146 92
rs7348267 1.1E−05 0.39 17% 32% 4 8 44 62 107 51
rs6032205 1.4E−05 0.39 17% 33% 4 8 44 62 104 50
kgp11768533 1.5E−05 2.37 48% 31% 32 5 85 66 37 50
rs502330 1.6E−05 0.07 1% 7% 0 0 2 18 153 103
rs1478682 1.7E−05 2.34 46% 29% 31 4 81 63 42 54
kgp11467007 1.8E−05 0.24 4% 14% 0 2 12 30 143 89
rs196295 1.9E−05 0.42 15% 31% 4 15 39 46 111 60
rs196343 2.0E−05 0.42 15% 31% 4 15 39 45 112 60
rs7217872 2.0E−05 0.36 10% 24% 1 7 29 43 125 71
rs1079303 2.2E−05 2.33 48% 31% 32 5 85 66 38 50
rs10501082 2.2E−05 2.33 48% 31% 32 5 85 66 38 50
rs6718758 2.2E−05 0.46 28% 45% 10 27 66 56 79 38
rs7948420 2.2E−05 0.46 27% 45% 12 24 81 61 82 36
kgp18432055 2.3E−05 3.61 18% 6% 5 0 46 14 104 106
rs10954782 2.4E−05 2.11 58% 40% 53 18 74 60 28 43
kgp9078300 2.7E−05 2.95 23% 10% 6 1 60 22 88 98
rs7928078 3.0E−05 2.30 48% 31% 31 5 85 66 38 50
kgp9884626 3.1E−05 ? 0% 5% 0 0 0 13 154 108
rs9579566 3.2E−05 0.11 1% 8% 0 1 3 18 152 102
indicates data missing or illegible when filed
TABLE 19
Allelic Model, Extreme Response Definition, Genome Wide Analysis (GALA, FORTE, and Combined cohorts)
GALA
Al- FORTE
Gene Odds Al- lele Odds
Loca- Ratio lele Freq; Ratio
Chromo- Posi- tions Fisher's (Minor Freq. (Con- Fisher's (Minor
Name some tio Gene(s Mutati (s) Exact Allel (Cas trols Exact Allel
kgp621435 11 75546691 UVRAG Silent INTRON 3.08E−03 0.21 3% 13% 2.29E−04 0.14
rs759458 2 65245365 SLC144, Missense— EXON 8.18E−05 2.97 36% 16% 4.98E−02 1.93
S
rs197523 21 19337261 CHODL, Silent, INTRON 5.54E−05 2.94 40% 19% 3.61E−02 1.99
CH Silen
rs7844274 8 72411302 ? ? ? 1.13E−03 0.42 21% 39% 1.57E−02 0.45
kgp107881 12 13898682 GRIN2B Silent INTRON 1.51E−03 0.00 0% 7% 7.96E−04 0.09
rs5918137 X 41113080 ? ? ? 1.69E−03 2.74 24% 10% 4.13E−02 2.05
kgp131253 2 1.38E+08 THSD7B Silent INTRON 1.04E−03 2.85 25% 10% 4.44E−03 3.45
kgp962733 17 90155 RPH3AL, Silent, INTRON 1.46E−03 0.32 8% 22% 1.58E−03 0.30
R Silen
rs196343 10 1.21E+08 BAG3 Silent INTRON 8.14E−05 0.30 11% 30% 7.18E−03 0.42
rs196295 10 1.21E+08 BAG3 Synonymo EXON 7.94E−05 0.30 11% 30% 1.09E−02 0.43
rs343087 12 66260924 HMGA2, Silent, INTRON, 3.77E−03 2.96 18% 7% 5.26E−03 3.70
H Silen E
kgp184320 9 1.09E+08 TMEM388 Silent UTR 3.76E−04 3.72 20% 6% 1.08E−02 4.35
rs7725112 5 1.74E+08 ? ? ? 4.85E−04 3.59 21% 7% 3.71E−02 2.61
rs7028906 9 1.08E+08 ? ? ? 8.10E−05 4.36 21% 6% 2.72E−02 3.65
rs9579566 13 30980265 ? ? ? 3.90E−04 0.00 0% 8% 1.68E−02 0.18
kgp23914 2 43425645 ? ? ? 7.83E−04 0.39 18% 36% 4.73E−03 0.41
kgp32029 12 13859947 GRIN2B Silent INTRON 8.78E−03 0.10 1% 7% 6.75E−04 0.09
kgp988462 2 2.07E+08 ? ? ? 5.91E−03 0.00 0% 6% 2.23E−02 0.00
kgp227932 X 92601576 ? ? ? 1.68E−03 0.47 34% 52% 4.17E−03 0.44
kgp568099 6 1.64E+08 ? ? ? 6.18E−04 0.43 29% 48% 2.57E−02 0.51
kgp810749 6 1.64E+08 ? ? ? 1.11E−03 0.45 35% 54% 2.91E−02 0.52
kgp114670 5 1.73E+08 STC2 Silent INTRON 6.44E−04 0.16 2% 13% 4.17E−03 0.26
kgp109485 20 44082511 ? ? ? 9.59E−03 0.49 20% 33% 4.00E−03 0.37
rs7217872 17 88988 RPH3AL, Silent, INTRON 2.31E−03 0.33 8% 22% 1.77E−03 0.32
R Silen
rs343092 12 65250940 HMGA2, Sileni, INTRON, 6.14E−03 2.81 17% 7% 8.40E−03 3.53
H Silen E
rs7948420 11 27276450 ? ? ? 4.80E−05 0.35 20% 42% 8.59E−03 0.46
rs9913349 17 68260070 ? ? ? 2.63E−03 2.30 32% 17% 3.61E−02 1.99
rs6718758 2 60328802 ? ? ? 6.51E−03 0.51 31% 47% 1.42E−02 0.48
FORTE COMBINED
Al- Al-
Al- lele Odds Al- lele
lele Freq; Ratio lele Freq; DD Dd dd
Freq. (Con- Fisher's (Minor Freq. (Con- DD (Con- Dd (Con- dd (Con-
Name (Cas trols Exact Allel (Cas trols (Cases) trol (Cases) trol (Cases) trol
kgp621435 97% 83% 1.51E−06 0.18 3% 14% 0 1 9 32 145 88
rs759458 64% 77% 2.38E−06 2.61 36% 18% 20 3 71 37 63 81
rs197523 63% 77% 2.67E−06 2.52 38% 20% 26 5 67 38 62 78
rs7844274 83% 69% 2.87E−06 0.40 19% 37% 4 18 50 53 100 50
kgp107881 99% 89% 5.83E−06 0.07 1% 8% 0 1 2 18 153 102
rs5918137 68% 81% 6.58E−06 2.72 29% 13% 22 8 44 15 88 98
kgp131253 76% 91% 6.88E−06 2.98 25% 10% 13 3 50 18 91 100
kgp962733 89% 71% 7.24E−06 0.34 10% 24% 1 7 28 44 125 70
rs196343 82% 66% 7.88E−06 0.39 15% 31% 4 15 39 45 112 60
rs196295 82% 66% 8.19E−06 0.39 15% 31% 4 15 39 46 111 60
rs343087 78% 93% 8.46E−06 3.40 20% 7% 12 0 39 17 103 104
kgp184320 84% 96% 1.53E−05 3.56 18% 6% 5 0 46 14 104 106
rs7725112 80% 91% 1.76E−05 3.17 20% 7% 5 1 53 16 97 104
rs7028906 86% 96% 1.76E−05 3.63 17% 5% 4 0 45 13 106 108
rs9579566 98% 91% 1.80E−05 0.11 1% 8% 0 1 3 18 152 102
kgp23914 76% 57% 1.81E−05 0.44 21% 38% 8 20 49 52 96 49
kgp32029 99% 88% 1.87E−05 0.11 1% 8% 0 1 3 18 150 101
kgp988462 100% 96% 1 93E−05 0.00 0% 5% 0 0 0 13 154 108
kgp227932 65% 44% 1.93E−05 0.47 35% 53% 32 41 42 47 78 33
kgp568099 70% 54% 1.94E−0S 0.46 30% 48% 13 27 65 61 76 33
kgp810749 66% 50% 1.96E−05 0.47 34% 53% 17 32 72 64 65 25
kgp114670 95% 83% 1.96E−05 0.25 4% 14% 0 2 12 30 143 89
kgp109485 85% 69% 2.02E−05 0.42 17% 33% 4 8 44 63 107 50
rs7217872 89% 71% 2.05E−05 0.36 10% 24% 1 7 29 43 125 71
rs343092 79% 93% 2.18E−05 3.24 20% 7% 11 0 39 17 105 104
rs7948420 67% 49% 2.27E−05 0.46 27% 45% 12 24 61 61 82 36
rs9913349 63% 77% 2.31E−05 2.34 35% 19% 15 5 78 35 62 81
rs6718758 75% 59% 2.36E−05 0.46 28% 45% 10 27 66 56 79 38
indicates data missing or illegible when filed
TABLE 20
Additive Model, Extreme Response Definition, Genome Wide Placebo Cohort Analysis
Placebo
Regres-
Gene sion DD Dd dd
Posi- Muta- Loca- Armitage Odds DD (Con- Dd (Con- dd (Con-
Name Chr tion Gene(s) tion tions(s) P Ratio (Cases) trols) (Cases) trols) (Cases) trols)
rs1978721 19 30966217 ZNF536 Silent INTRON 9.89E−09 35.3 0 0 11 2 12 77
kgp7344529 19 30967564 ZNF536 Silent INTRON 9.89E−09 35.3 0 0 11 2 12 77
rs7252241 19 309637836 ZNF536 Silent INTRON 9.89E−09 35.3 0 0 11 2 12 77
rs1978720 19 30968371 ZNF536 Silent INTRON 9.89E−09 35.3 0 0 11 2 12 77
kgp146166 19 30965980 ZNF536 Silent INTRON 1.92E−07 13.8 0 0 14 8 9 71
rs8112863 19 30965063 ZNF536 Silent INTRON 2.37E−07 13.6 0 0 14 8 9 70
kgp2877482 6 1644577 GMDS, GMDS Silent, Silent INTRON 3.47E−07 17.2 0 0 11 4 12 75
kgp7851536 15 27950322 ? ? ? 3.76E−07 ? 0 0 7 0 16 79
kgp9348779 15 101900592 PCSK6, PCSK6, Silent, Silent, INTRON 3.76E−07 ? 0 0 7 0 16 79
PCSK6, PCSK6, Silent, Silent,
PCSK6, PCSK6 Silent, Silent
rs2289333 15 40617209 ? ? ? 5.68E−07 17.9 1 0 9 3 13 76
kgp2471573 15 40633138 C15orf52 Synonymous_ASA EXON 5.68E−07 17.9 1 0 9 3 13 76
kgp8598661 6 1627678 GMDS, GMDS Silent, Silent INTRON 6.01E−07 12.5 1 0 11 6 11 73
rs16846841 2 197063250 ? ? ? 6.12E−07 41.6 0 0 8 3 15 78
rs7565256 2 79227275 ? ? ? 6.17E−07 9.1 4 0 14 22 5 56
kgp12396787 22 27267611 ? ? ? 7.21E−07 41.1 0 0 8 1 15 77
kgp6535349 15 40614200 ? ? ? 7.54E−07 24.4 0 0 9 2 14 76
kgp9775757 1 23068465 EPHB2, EPHB2 Silent, Silent INTRON 1.13E−06 9.2 3 0 15 22 5 57
kg2151888 2 79295288 ? ? ? 1.87E−06 8.2 3 0 13 19 6 60
kgp4985243 7 136556162 CHRM2, CHRM2, Silent, Silent, INTRON 2.25E−06 9.3 1 0 13 11 9 68
CHRM2, CHRM2, Silent, Silent,
CHRM2, CHRM2, Silent, Silent,
CHRM2, CHRM2 Silent, Silent
kgp6870400 2 79278036 ? ? ? 2.38E−06 7.4 4 0 13 22 6 57
rs1077476 15 40619743 ? ? ? 2.53E−06 13.1 1 0 9 4 13 74
kgp2136475 15 40623593 ? ? ? 2.53E−06 13.1 1 0 9 4 13 74
rs4935590 10 57059483 ? ? ? 2.59E−06 8.2 2 0 11 12 9 67
rs16907220 10 57059690 ? ? ? 2.59E−06 8.2 2 0 12 12 9 67
rs1073665 10 57061057 ? ? ? 2.59E−06 8.2 3 0 12 12 9 67
rs4477500 12 128645821 ? ? ? 2.62E−06 7.3 3 2 10 37 3 39
kgp9016053 17 69386788 ? ? ? 2.87E−06 10.5 1 0 10 7 10 71
kgp2617488 3 11849777 TAMM41 Silent INTRON 2.88E−06 ? 0 0 6 0 17 79
kgp3537954 5 103927513 ? ? ? 2.88E−06 74945934087673200.0 0 0 6 0 17 79
kgp9400093 5 104031832 ? ? ? 2.88E−06 74945934087673200.0 0 0 6 0 17 79
kgp3681524 7 145920329 CNTNAP2 Silent INTRON 2.88E−06 45450941538370800.0 0 0 6 0 17 79
kgp788303 10 23545459 ? ? ? 2.88E−06 74935934087672700.0 0 0 6 0 17 79
kgp7824246 12 11333716 ? ? ? 2.88E−06 74935934087672700.0 0 0 6 0 17 79
kgp27533766 12 65501698 WIF1 Silent INTRON 2.88E−06 74935934087672700.0 0 0 6 0 17 79
kgp4089310 18 7309451 ? ? ? 2.88E−06 ? 0 0 6 0 17 79
rs17225585 17 69370430 ? ? ? 3.05E−06 10.2 1 0 11 7 11 69
rs13104183 4 113323534 ALPK1, ALPK1, Silent, Silent INTRON, EXON 3.43E−06 6.7 4 0 10 16 8 63
ALPK1 Silent
kgp11962292 10 88223587 WAPAL Silent INTRON 3.61E−06 10.5 1 0 10 6 12 73
rs3934982 2 242926558 ? ? ? 3.66E−06 11.5 1 0 9 5 12 74
kgp896539 3 135473872 ? ? ? 3.77E−06 10.6 0 0 12 8 10 71
rs6743255 2 205363596 ? ? ? 4.33E−06 7.7 2 0 13 15 8 64
kgp5046752 2 179650234 TTN, TTN, TTN Silent, Silent, INTRON 4.67E−06 34.1 0 0 7 1 16 78
TTN, TTN Silent, Silent,
Silent
kgp3420885 13 112188913 ? ? ? 4.67E−06 34.1 0 0 7 1 16 78
kgp3423367 19 54113722 ? ? ? 4.67E−06 34.1 0 0 7 1 16 78
kgp9522435 19 30951753 ZNF536 Silent INTRON 4.71E−06 20.5 0 0 8 2 15 77
kgp5544649 19 30958606 ZNF536 Silent INTRON 4.71E−06 20.5 0 0 8 2 15 77
kgp3185857 22 27269249 ? ? ? 4.71E−06 20.5 0 0 8 2 15 77
kgp5863276 22 27274898 ? ? ? 4.71E−06 20.5 0 0 8 2 15 77
rs17825388 17 69380584 ? ? ? 4.74E−06 9.2 1 0 11 8 11 71
rs1942396 18 69347308 ? ? ? 4.74E−06 9.2 1 0 11 8 11 71
kgp2575625 2 218219226 DIRC3 Silent INTRON 5.23E−06 8.6 1 0 12 10 10 69
kgp11688655 2 218219697 DIRC3 Silent INTRON 5.23E−06 8.6 1 0 12 10 10 69
kgp3778675 2 218226516 DIRC3 Silent INTRON 5.23E−06 8.6 1 0 12 10 10 69
rs10488907 4 113312105 ALPK1, ALPK1, Silent, Silent, INTRON, EXON 5.36E−06 7.6 2 0 12 13 9 66
ALPK1 Silent
kgp2832863 3 8820301 ? ? ? 5.38E−06 33.7 0 0 7 1 16 77
kgp6643157 3 13145604 ? ? ? 5.46E−06 20.3 0 0 8 2 15 76
kgp4292871 22 27274445 ? ? ? 5.46E−06 20.3 0 0 8 2 15 76
rs6643055 X 111782861 ? ? ? 5.65E−06 18.3 1 0 7 2 15 77
rs12005792 9 87236739 ? ? ? 6.46E−06 6.8 3 1 15 22 5 56
rs882829 15 40607689 ? ? ? 6.98E−06 10.6 1 0 9 5 13 74
kgp1305638 6 122195448 ? ? ? 7.74E−06 29.6 1 0 6 1 16 78
rs6673115 1 23069649 EPHB2, EPHB2 Silent, Silent INTRON 8.25E−06 6.7 5 1 14 30 4 48
kgp7380442 22 28746343 TTC28 Silent INTRON 8.80E−06 ? 1 0 5 0 17 79
kgp4898364 22 29092726 CHEK2, CHEK2, Silent, Silent, INTRON 8.80E−06 ? 1 0 5 0 17 79
CHEK2 Silent
kgp9420863 1 105167334 ? ? ? 9.42E−06 9.0 0 0 13 10 10 69
kgp100271 1 105186472 ? ? ? 9.42E−06 9.0 0 0 13 10 10 69
kgp4009576 1 105189899 ? ? ? 9.42E−06 9.0 0 0 13 10 10 69
kgp11130156 12 20871256 SLCO1C1, SLCO1C1, Silent, Silent, INTRON 9.52E−06 6.4 2 1 13 13 8 69
SLCO1C1, SLCO1C1 Silent, Silent
rs10746192 12 81342162 PPFIA2, PPFIA2, Silent, Silent, INTRON 9.87E−06 8.0 8 5 15 45 0 29
PPFIA2, PPFIA2, Silent, Silent,
PPFIA2, PPFIA2, Silent, Silent,
PPFIA2 Silent
kgp8919080 7 84958459 ? ? ? 9.94E−06 8.9 1 0 10 7 12 72
TABLE 21
Allelic Model, Extreme Response Definition, Genome Wide Placebo Cohort Analysis
Placebo
Odds Allele
Gene Ratio Allele Freq. DD Dd dd
Posi- Muta- Loca- Fisher's (Minor Freq. (Con- DD (Con- Dd (Con- dd (Con-
Name Chr tion Gene(s) tion tions(s) Exact P Allele) (Cases) trols) (Cases) trols) (Cases) trols) (Cases) trols)
kgp106385 3 196573166 ? ? ? 1.00E−06 0.1 7% 44% 0 17 3 35 20 27
rs1978721 19 30966217 ZNF536 Silent INTRON 1.49E−06 24.5 24% 1% 0 0 11 2 12 77
kgp734452 19 30967564 ZNF536 Silent INTRON 1.49E−06 24.5 24% 1% 0 0 11 2 12 77
rs7252241 13 30967836 ZNF536 Silent INTRON 1.49E−06 24.5 24% 1% 0 0 11 2 12 77
rs1978720 19 30968371 7NF536 Silent INTRON 1.49E−06 24.5 24% 1% 0 0 11 2 12 77
kgp183404 3 196579489 ? ? ? 2.26E−06 0.1 7% 42% 0 14 3 38 20 27
kgp860737 17 20459947 ? ? ? 4.36E−06 0.0 2% 35% 0 10 1 35 20 34
rs2289333 15 40617209 ? ? ? 5.79E−06 16.2 24% 2% 1 0 9 3 13 76
kgp247157 15 40633138 C15orf52 Synonymo EXON 5.79E−06 16.2 24% 2% 1 0 9 3 13 76
rs7565256 2 79227275 ? ? ? 7.04E−06 5.6 48% 14% 4 0 14 22 5 56
kgp859866 6 1627678 GMDS, GM Silent, Sile INTRON 8.30E−06 10.0 28% 4% 1 0 11 6 11 73
rs1310418 4 113323634 ALPK1, ALP Silent, Sile INTRON, E 9.26E−06 6.1 41% 10% 4 0 10 16 8 63
rs4477500 12 128645821 ? ? ? 9.70E−06 4.9 64% 26% 9 2 10 37 3 39
kgp359896 4 7649861 SORCS2 Silent INTRON 9.97E−06 0.0 2% 31% 0 7 1 35 22 37
kgp111645 17 20459328 ? ? ? 1.07E−05 0.1 4% 35% 0 9 2 36 21 32
kgp146166 19 30965980 ZNF536 Silent INTRON 1.22E−05 8.2 30% 5% 0 0 14 8 9 71
rs8112863 19 30965063 ZNF536 Silent INTRON 1.38E−05 8.1 30% 5% 0 0 14 8 9 70
rs2555629 4 175430288 HPGD, HPG Silent, Sile INTRON, E 1.40E−05 4.6 61% 25% 11 4 6 32 6 43
kgp215188 2 79295288 ? ? ? 1.44E−05 5.6 43% 12% 3 0 13 19 6 60
kgp553777 20 35531097 SAMHD1 Silent INTRON 1.68E−05 5.5 41% 11% 4 1 11 15 8 62
kgp400479 20 35539858 SAMHD1 Silent INTRON 1.68E−05 5.5 41% 11% 4 1 11 16 8 62
kgp977575 1 23068465 EPHB2, EP Silent, Sile INTRON 1.68E−05 5.2 46% 14% 3 0 15 22 5 57
kgp687040 2 79278036 ? ? ? 1.68E−05 5.2 46% 14% 4 0 13 22 6 57
rs763318 4 12963674 ? ? ? 1.70E−05 5.4 83% 47% 15 20 8 33 0 25
rs4935590 10 57059483 ? ? ? 1.73E−05 6.5 35% 8% 2 0 12 12 9 67
rs1690722 10 57059690 ? ? ? 1.73E−05 6.5 35% 8% 2 0 12 12 9 67
rs1073665 10 57061057 ? ? ? 1.73E−05 6.5 35% 8% 2 0 12 12 9 67
kgp596929 4 12976777 ? ? ? 1.73E−05 4.5 70% 34% 11 10 10 33 2 36
kgp287748 5 1644677 GMDS, GM Silent, Sile INTRON 1.81E−05 12.1 24% 3% 0 0 11 4 12 75
rs4916561 3 196576109 ? ? ? 1.84E−05 0.1 7% 38% 0 12 3 36 20 30
kgp228237 X 31244702 DMD, DMD Silent, Sile INTRON 1.91E−05 0.1 2% 30% 0 17 1 14 22 48
rs1077476 15 40619743 ? ? ? 2.00E−05 11.9 24% 3% 1 0 9 4 13 74
kgp213647 15 40623593 ? ? ? 2.00E−05 11.9 24% 3% 1 0 9 4 13 74
kgp785153 15 27960322 ? ? ? 2.04E−05 ? 15% 0% 0 0 7 0 16 79
kgp934877 15 101900592 PCSK6, PCS Silent, Sile INTRON 2.04E−05 ? 15% 0% 0 0 7 0 16 79
indicates data missing or illegible when filed
Example 13 Association Analysis Corrected for Ancestry A Principal Components Analysis (PCA) was performed in order to investigate potential population stratification among cases and controls. Sample-specific Eigen values were calculated to produce an output of 1st and 2nd Principal Components which can be used to infer patient ancestry.
An association analysis was performed using an Additive Genetic Model with Principal Components Analysis correction for population stratification; results are presented in Table 22.
TABLE 22
Regression, Additive Model, Corrected for ancestry by PCA
GALA FORTE
Al- Al-
Gene Al- lele Al- lele
Loca- Regres- lele Freq. Regres- lele Freq.
Posi- tions sion Freq. (Con- sion Freq. (Con-
Name Chr tio Gene(s Mutati (s) P (Cases) trols) P (Cases) trol
kgp244155 2 1.74E+08 ? ? ? 1.91E−05 0% 5% 1.28E−02 0% 3%
kgp250265 13 79972606 RBM26 Silent INTRON 1.47E−04 0% 3% 2.92E−04 0% 4%
kgp120089 2 73759636 ALMS1 Silent INTRON 1.49E−04 0% 4% 2.26E−04 1% 6%
rs1688600 7 78021500 MAGI2 Silent INTRON, 1.93E−03 20% 11% 3.01E−05 20% 5%
E
kgp259528 13 80027089 ? ? ? 4.30E−04 0% 3% 2.86E−04 0% 4%
kgp111415 20 35283733 NDRF3, Silent, INTRON 2.69E−03 2% 7% 3.18E−05 1% 6%
N Sile
kgp345087 16 57268931 RSPRV1 Silent INTRON 5.32E−03 1% 4% 1.47E−05 0% 7%
kgp229967 20 16933074 ? ? ? 5.73E−03 2% 5% 3.71E−05 1% 8%
kgp122303 5 27037978 CDH9 Silent INTRON 2.71E−03 1% 5% 7.14E−06 2% 9%
kgp962733 17 90155 RPH3AL, Silent, INTRON 6.18E−04 10% 21% 3.96E−03 11% 20%
R Sile
rs1025179 7 78025427 MAGI2 Silent INTRON, 1.71E−03 20% 11% 3.76E−05 19% 5%
E
rs2816838 10 52714759 ? ? ? 1.20E−03 14% 23% 1.38E−03 11% 22%
kgp623694 2 60301030 ? ? ? 3.77E−04 31% 44% 4.52E−03 26% 39%
kgp235638 16 19771577 IQCK Silent INTRON 1.76E−04 12% 22% 1.39E−03 14% 26%
kgp773039 16 19740243 IQCK Silent INTRON 2.39E−04 13% 22% 1.06E−03 14% 28%
kgp470585 12 19907696 ? ? ? 2.12E−05 30% 47% 3.99E−02 33% 43%
rs7191155 16 19800213 IQCK Missense EXON 2.52E−04 12% 22% 1.18E−03 14% 28%
kgp803072 8 6328607 MCPH1 Silent INTRON 1.62E−02 2% 5% 1.78E−05 1% 7%
rs9931167 16 19792598 IQCK Silent INTRON 2.53E−04 12% 22% 1.39E−03 14% 26%
rs7217872 17 88988 RPH3AL, Silent, INTRON 1.35E−03 11% 20% 3.00E−03 11% 21%
R Sile
rs1164812 16 19820694 IQCK Silent INTRON 3.15E−04 12% 22% 1.08E−03 14% 26%
rs3829539 16 19722366 C16orf88 Silent INTRON 2.51E−04 12% 22% 1.40E−03 15% 26%
rs2660214 10 52732452 ? ? ? 1.68E−03 14% 23% 1.84E−03 11% 22%
rs6718758 2 60328802 ? ? ? 3.14E−03 33% 45% 4.38E−04 28% 44%
kgp105944 1 2.16E+08 USH2A Silent INTRON 2.20E−05 0% 5% 2.84E−02 1% 5%
rs1858973 16 19743649 IQCK Silent INTRON 3.15E−04 12% 22% 1.38E−03 15% 26%
kgp881785 6 32744440 ? ? ? 6.70E−04 36% 49% 4.72E−04 42% 60%
kgp385418 16 19721806 C16orf88 Silent INTRON 3.14E−04 12% 22% 1.29E−03 14% 26%
kgp297947 10 18397332 ? ? ? 3.45E−03 2% 7% 2.96E−04 2% 8%
rs543122 3 1.24E+08 KALRN, Silent, INTRON 2.87E−05 41% 57% 1.56E−03 44% 57%
KA Sile
kgp252161 1 23758427 ASAP3, Silent, INTRON 1.03E−03 0% 3% 3.25E−03 0% 3%
AS Sile
rs8055485 16 19750051 IQCK Silent INTRON 3.15E−04 12% 22% 1.51E−03 15% 26%
rs9931211 16 19813605 IQCK Silent INTRON 3.15E−04 12% 22% 1.51E−03 15% 26%
rs9817308 3 1.24E+08 KALRN, Silent, INTRON 2.46E−05 41% 58% 3.14E−02 45% 57%
KA Sile
kgp621435 11 75546691 UVRAG Silent INTRON 4.73E−03 5% 11% 1.34E−04 4% 13%
rs9579566 13 30980265 ? ? ? 1.22E−04 2% 8% 1.55E−02 2% 7%
kgp506839 16 19756348 IQCK Silent INTRON 1.52E−04 10% 27% 2.10E−03 20% 34%
rs6497396 16 19735697 IQCK Silent INTRON 2.47E−04 13% 23% 1.48E−03 16% 29%
rs7228827 18 76900411 ATP9B Silent INTRON 2.53E−04 21% 11% 8.65E−03 20% 11%
rs950928 16 19824638 IQCK Silent INTRON 5.52E−04 13% 22% 1.64E−03 15% 26%
rs7579987 2 60307009 ? ? ? 3.85E−03 36% 47% 4.94E−04 31% 48%
kgp103051 11 99881768 CNTN5, Silent, INTRON, 3.08E−03 10% 18% 1.45E−03 7% 16%
C Sile E
kgp10910 16 19803199 IQCK Silent INTRON 4.44E−04 12% 21% 1.39E−03 14% 26%
kgp168875 21 43016736 ? ? ? 1.94E−03 5% 13% 3.96E−03 3% 11%
kgp11002 11 1.18E+08 CD3G Silent INTRON 4.13E−03 1% 3% 2.94E−04 0% 4%
rs6895094 5 1.41E+08 ARAP3 Silent INTRON 6.18E−04 38% 52% 1.33E−02 35% 48%
rs2074037 16 19725130 C16orf88 Silent INTRON 5.92E−04 13% 22% 1.25E−03 15% 26%
kgp270001 16 19750275 IQCK Silent INTRON 2.51E−04 13% 23% 2.90E−03 15% 28%
COMBINED
Al-
Al- lele
Regres- lele Freq. DD Dd dd
sion Freq. (Con- DD (Con- Dd (Con- dd (Con-
Name P (Cases) trols) (Cases trol (Cases trol (Cases trol
kgp244155 2.24E−07 0% 4% 0 0 3 16 396 165
kgp250265 2.54E−07 0% 4% 0 0 1 13 397 167
kgp120089 6.38E−07 0% 4% 0 0 3 16 396 165
rs1688600 8.60E−07 20% 9% 6 2 147 28 246 149
kgp259528 6.77E−07 0% 3% 0 0 1 12 398 168
kgp111415 9.79E−07 1% 8% 0 1 11 21 388 158
kgp345087 1.26E−06 1% 5% 0 0 5 17 394 164
kgp229967 1.48E−06 1% 6% 0 0 11 23 388 158
kgp122303 1.71E−06 1% 6% 0 0 10 22 386 159
kgp962733 1.87E−06 10% 21% 6 7 71 61 320 113
rs1025179 1.98E−06 20% 9% 6 2 145 29 248 150
rs2816838 2.41E−06 13% 23% 4 8 92 67 303 106
kgp623694 2.86E−06 28% 42% 30 34 166 85 203 62
kgp235638 2.92E−06 13% 23% 4 5 98 75 297 101
kgp773039 3.08E−06 13% 23% 4 5 99 74 295 101
kgp470585 3.44E−06 31% 46% 41 38 169 89 189 54
rs7191155 4.02E−06 13% 23% 4 5 97 74 295 101
kgp803072 4.03E−06 1% 8% 0 1 9 18 388 162
rs9931167 4.16E−06 13% 23% 4 5 98 74 297 101
rs7217872 4.20E−06 11% 21% 6 7 74 61 319 113
rs1164812 4.25E−06 13% 23% 4 5 97 74 297 102
rs3829539 4.53E−06 13% 23% 4 5 98 74 296 101
rs2660214 4.68E−06 13% 23% 4 8 94 66 301 107
rs6718758 4.69E−06 31% 44% 35 38 175 85 189 58
kgp105944 4.94E−06 1% 5% 0 0 6 18 391 163
rs1858973 5.09E−06 13% 23% 4 5 99 74 295 102
kgp881785 5.13E−06 39% 53% 50 44 208 103 135 34
kgp385418 5.23E−06 13% 23% 4 5 98 74 297 102
kgp297947 5.49E−06 2% 7% 0 0 16 26 382 155
rs543122 5.65E−06 42% 57% 70 54 195 97 131 29
kgp252161 5.89E−06 0% 3% 0 0 2 12 397 169
rs8055485 5.77E−06 13% 23% 4 5 98 74 296 102
rs9931211 5.77E−06 13% 23% 4 5 98 74 296 102
rs9817308 5.89E−06 43% 57% 71 54 199 96 127 29
kgp621435 6.31E−06 5% 12% 0 2 37 39 361 140
rs9579566 6.66E−06 2% 8% 0 1 18 27 381 153
kgp506839 6.70E−06 18% 29% 10 12 126 82 262 86
rs6497396 6.74E−06 14% 23% 6 6 102 77 290 98
rs7228827 6.90E−06 21% 11% 20 1 124 37 254 143
rs950928 6.96E−06 14% 24% 4 5 102 75 293 100
rs7579987 7.14E−06 33% 47% 40 41 134 87 175 52
kgp103051 7.23E−06 8% 17% 3 6 61 50 334 123
kgp10910 7.43E−06 13% 23% 4 5 98 73 297 102
kgp168875 7.70E−06 4% 11% 1 2 50 37 368 142
kgp11002 8.07E−06 0% 4% 0 0 3 13 394 167
rs6895094 8.17E−06 37% 51% 56 46 181 92 161 43
rs2074037 8.40E−06 14% 23% 4 5 101 73 294 101
kgp270001 8.56E−06 14% 24% 6 6 102 76 291 98
indicates data missing or illegible when filed
Example 14 Regression Analysis Regression analysis was conducted using an additive genetic model to identify additional clinical and genetic variants that are highly associated with response after correction for the most significantly associated variables.
For clinical factors, regression analyses revealed two highly associated clinical covariates: “Log number of relapses in the last two years” significantly associated with response to glatiramer acetate (combined cohorts p-value 3.6×10−32, odds ratio 14.5 (95% CI 8.6-24.4)) and “Baseline Expanded Disability Status Scale (EDSS) Score” (combined cohorts p-value 5.9×10−10, odds ratio 0.62 (95% CI 8.6-24.4)) with higher baseline EDSS scores (increased MS disability) associated with increased likelihood of non-response to glatiramer acetate. Importantly, these clinical factors were significantly associated with glatiramer acetate response in both the GALA and FORTE patient cohorts.
TABLE 23
Clinical co-variates associated with response to glatiramer acetate.
GALA cohort (N = 318) FORTE cohort (N = 262) COMBINED cohorts (N = 580)
Odds P- Odds P- Odds P-
Variable Ratio (95% CI) Value Ratio (95% CI) Value Ratio (95% CI) Value
Log of No. of 16.78 8.4-33.4 2.3E−21 53.19 14.8-191.7 1.4E−11 14.50 8.6-24.4 3.6E−32
Relapses in
Last 2 Years
Baseline EDSS 0.62 0.5-0.8 3.0E−06 0.71 0.5-0.9 0.010 0.62 0.5-0.7 5.9E−10
Score
Age 0.97 0.9-1.0 0.034 0.98 0.9-1.0 0.22 0.97 1.0-1.0 0.012
PCA Component 3 Inf. 0.06 Inf. 0.07 Infinity 0.017
(EV = 2.41024)
No. of Gd-T1 0.97 0.9-1.0 0.10 0.96 0.9-1.0 0.11 0.97 0.9-1.0 0.034
Lesions at
Baseline
Results of regression analyses for the Additive Models are presented in Tables 24-27.
In some embodiments, all of the genetic markers presented in Tables 24-27 are identified as predictive of response to glatiramer acetate.
TABLE 24
Regression Analysis, Additive Model (GALA cohort)
COMBINED
Predictor Chr Position Gene P-Value Odds Ratio
rs16886004 7 78021500 MAGI2 3.10E−07 2.79
kgp26026546 13 79972606 7.45E−07 0.03
rs10251797 7 78025427 MAGI2 7.93E−07 2.67
kgp8110667 22 32716792 9.48E−07 Infinity
kgp11210241 3 38537237 9.74E−07 Infinity
rs17687961 22 32716927 9.74E−07 Infinity
kgp12008955 2 73759636 1.08E−06 0.08
kgp24415534 2 1.74E+08 1.08E−06 0.08
kgp5976729 22 32675303 2.12E−06 Infinity
kgp25952891 13 80027089 2.38E−06 0.04
rs543122 3 1.24E+08 2.81E−06 0.54
kgp6236949 2 60301030 3.70E−06 0.54
rs9817308 3 1.24E+08 4.60E−06 0.55
kgp10372946 10 1.34E+08 4.62E−06 10.53
kgp8817856 6 32744440 4.90E−06 0.53
kgp11328629 10 1.21E+08 5.02E−06 2.95
kgp4705854 12 19907696 5.19E−06 0.55
rs4143493 6 51829939 5.24E−06 4.21
kgp3450875 16 57268931 5.60E−06 0.12
kgp1688752 21 43016736 5.79E−06 0.33
kgp9627338 17 90155 6.00E−06 0.45
rs17577980 6 32359821 6.15E−06 2.36
kgp3418770 10 59425598 6.31E−06 10.31
kgp2299675 20 16933074 6.55E−06 0.19
rs6718758 2 60328802 6.61E−06 0.55
rs7579987 2 60307009 6.71E−06 0.55
kgp10594414 1 2.16E+08 6.80E−06 0.14
rs10498793 6 51829707 7.20E−06 4.14
rs2816838 10 52714759 7.32E−06 0.46
kgp12230354 5 27037978 7.64E−06 0.19
rs13394010 2 60302746 8.16E−06 0.56
rs11029892 11 27269546 8.23E−06 1.94
kgp2356388 16 19771577 8.28E−06 0.46
rs11691553 2 60303554 8.55E−06 0.56
kgp5564995 6 26414060 9.08E−06 2.88
rs6895094 5 1.41E+08 9.18E−06 0.57
kgp10352965 7 30647900 9.40E−06 7.44
kgp26116630 6 48158833 9.42E−06 16.38
kgp7059449 2 41255455 9.98E−06 4.93
rs10203396 2 60305110 1.01E−05 0.56
kgp11843177 11 27316568 1.01E−05 1.95
rs9579556 13 30980265 1.04E−05 0.26
kgp11141512 20 35283733 1.06E−05 0.21
TABLE 25
Regression Analysis, Additive Model Corrected for Log Relapse and EDSS (GALA, FORTE, Combined cohorts)
Gene GALA FORTE COMBINED
Chromo- Posi- Muta- Loca- P- Odds P- Odds P- Odds
Name some tion Gene(s) tion tions (s) value* Ratio value* Ratio value* Ratio
kgp8817856 6 32744440 ? ? ? 8.04E−29 0.48 1.18E−16 0.32 9.16E−43 0.39
rs454748 6 32213210 ? ? ? 1.60E−30 2.32 4.89E−14 1.78 6.67E−42 2.16
kgp5447044 6 26501768 BTN1A1 Silent INTRON 2.47E−29 0.31 2.37E−14 0.41 1.55E−41 0.35
rs16901784 6 26555433 ? ? ? 1.19E−29 0.29 2.19E−14 0.40 1.64E−41 0.34
rs2143466 6 32309323 C6orf10 Silent INTRON 6.41E−30 2.18 6.55E−14 1.75 1.88E−41 2.10
kgp9938485 6 27021173 ? ? ? 4.37E−29 0.42 5.52E−14 0.50 2.22E−41 0.42
rs3799383 6 26510748 ? ? ? 3.25E−29 0.31 2.37E−14 0.41 2.65E−41 0.34
rs4897704 8 1.35E+08 ? ? ? 6.20E−32 2.67 7.64E−14 1.72 2.78E−41 2.05
kgp3478190 8 69080975 PREX2 Silent INTRON 2.18E−29 2.07 4.90E−14 1.95 2.80E−41 2.09
rs2820263 6 1.05E+08 ? ? ? 8.15E−29 1.80 1.40E−15 2.53 2.82E−41 2.09
kgp12230354 5 27037978 CDH9 Silent INTRON 1.39E−28 0.13 5.86E−15 0.13 2.82E−41 0.12
rs9393727 6 26500011 ? ? ? 2.92E−29 0.31 2.87E−14 0.41 3.25E−41 0.34
kgp31017880 X 97136288 ? ? ? 3.71E−30 19.90 5.62E−14 Infinity 3.34E−41 24.31
kgp3438641 5 98186154 ? ? ? 1.24E−29 4.24 6.31E−15 7.61 3.46E−41 4.51
kgp12113592 5 98160214 ? ? ? 2.07E−29 4.18 6.70E−15 7.53 3.54E−41 4.45
rs9650120 8 1.35E+08 ? ? ? 6.72E−31 2.55 3.20E−14 1.90 4.40E−41 2.08
kgp3931548 5 98146468 ? ? ? 1.51E−29 4.17 6.31E−15 7.61 4.59E−41 4.45
rs727637 5 98213991 CHD1 Silent INTRON 1.51E−29 4.17 6.31E−15 7.61 4.59E−41 4.45
kgp1892256 5 98257441 CHD1 Silent INTRON 1.51E−29 4.17 6.31E−15 7.61 4.59E−41 4.45
rs9501224 6 32792910 TAP2 Silent INTRON 5.89E−29 2.07 7.52E−16 3.15 4.80E−41 2.24
kgp11199573 2 2.02E+08 ? ? ? 4.05E−29 2.00 5.40E−15 2.23 4.97E−41 2.04
kgp7903189 5 98229104 CHD1 Silent INTRON 1.15E−29 3.43 5.21E−15 7.77 5.73E−41 3.90
rs2820259 6 1.05E+08 ? ? ? 7.65E−29 1.80 8.55E−15 2.20 5.90E−41 1.99
rs2857103 6 32791299 TAP2 Silent INTRON 5.55E−29 2.13 7.52E−16 3.15 6.22E−41 2.27
kgp9421884 19 11049860 ? ? ? 8.34E−28 0.39 1.80E−15 0.24 6.64E−41 0.29
rs6920256 6 26537801 ? ? ? 8.77E−29 0.35 2.37E−14 0.41 6.74E−41 0.36
kgp1688752 21 43016736 ? ? ? 7.35E−30 0.22 2.38E−14 0.30 7.23E−41 0.28
kgp6754792 6 26456074 ? ? ? 1.63E−29 0.25 1.45E−13 0.49 7.65E−41 0.34
kgp95865 9 14204068 NFIB, NFIB, Silent, Sile INTRON 6.17E−29 3.29 2.80E−14 4.31 7.69E−41 3.78
rs241451 6 32796480 TAP2, TAP2 Silent, Sile INTRON 6.05E−29 2.11 2.29E−15 2.80 8.11E−41 2.15
indicates data missing or illegible when filed
TABLE 26
Regression Analysis, Additive Model Corrected for top SNP rs1686004 (GALA, FORTE, and Combined cohorts)
Gene GALA FORTE COMBINED
Posi- Muta- Loca- P- Odds P- Odds P- Odds
Name Chr tion Gene(s) tion tions(s) value Ratio value Ratio value Ratio
kgp6996560 13 110124242 ? ? ? 6.61E−05 0.17 2.43E−08 0.02 2.03E−11 0.09
rs4143493 6 51829939 PKHD1, PKHD1 Silent, Silent INTRON 8.56E−05 3.34 3.58E−08 8.13 2.15E−11 4.50
kgp28541695 15 24935550 ? ? ? 4.99E−07 ~Infinity 2.77E−06 5.87 2.93E−11 17.52
rs10498793 6 51829707 PKHD1, PKHD1 Silent, Silent INTRON 8.56E−05 3.34 5.18E−08 7.79 3.18E−11 4.50
kgp4705854 12 19907696 ? ? ? 6.52E−07 0.47 3.84E−06 0.54 3.31E−11 0.53
kgp6236949 2 60301030 ? ? ? 2.13E−05 0.55 7.45E−07 0.53 3.61E−11 0.53
kgp12230354 5 27037973 CDH9 Silent INTRON 8.6E−05 0.18 1.21E−08 0.10 3.62E−11 0.16
kgp29794723 10 18397332 ? ? ? 6.52E−05 0.26 5.1E−08 0.13 3.63E−11 0.20
kgp971582 6 51922703 PKHD1, PKHD1 Synonymous_N529N, EXON 4.38E−05 3.35 1.51E−07 5.24 4.17E−11 3.96
Synonymous_NS29N
kgp4812831 6 51910905 PKHD1, PKHD1 Missense_N830S, EXON 4.38E−05 3.35 1.63E−07 5.34 4.7E−11 3.99
Missense_N830S
kgp4162414 6 51868165 PKHD1, PKHD1 Silent, Silent INTRON 5.42E−05 3.29 1.6E−07 5.34 5.5E−11 3.96
kgp2683306 7 28560259 CREB5, CREB5, Silent, Silent, INTRON 1.25E−05 3.03 4.92E−07 3.62 5.55E−11 3.15
CREB5 Silent
rs7579987 2 60307009 ? ? ? 0.000169 0.62 5.22E−08 0.44 5.73E−11 0.54
kgp9627338 17 90155 RPH3AL, RPH3AL, Silent, Silent, INTRON 3.23E−06 0.44 1.19E−06 0.45 5.92E−11 0.44
RPH3AL, RPH3AL Silent, Silent
kgp11328629 10 120711084 ? ? ? 5.3E−05 2.68 9.89E−08 4.12 6.08E−11 3.07
rs2816838 10 52714759 ? ? ? 5.23E−05 0.50 2.7E−07 0.40 6.29E−11 0.45
kgp24415534 2 174156875 ? ? ? 1.71E−06 0.05 5.58E−06 0.21 6.35E−11 0.09
rs10203396 2 60305110 ? ? ? 0.000191 0.63 5.5E−08 0.44 7.36E−11 0.54
rs13394010 2 60302746 ? ? ? 0.000193 0.63 5.22E−08 0.44 7.44E−11 0.54
rs6718758 2 60328802 ? ? ? 0.000165 0.63 8.83E−08 0.45 7.74E−11 0.54
rs11691553 2 60303554 ? ? ? 0.000235 0.63 4.41E−08 0.44 7.92E−11 0.54
kgp1009249 12 19838534 ? ? ? 1.96E−05 0.43 2.46E−06 0.56 8.26E−11 0.49
rs13419758 2 60302920 ? ? ? 0.000177 0.63 7.51E−08 0.45 8.34E−11 0.55
kgp9320791 2 60309952 ? ? ? 0.000191 0.63 6.84E−08 0.45 9.04E−11 0.55
rs11029892 11 27269546 ? ? ? 6.68E−05 1.82 1.98E−07 2.22 9.28E−11 1.98
kgp2350730 1 88444077 ? ? ? 2.24E−06 4.82 3.98E−06 2.43 9.28E−11 3.62
kgp8192546 12 19903173 ? ? ? 5.84E−07 0.43 4.85E−06 0.64 9.46E−11 0.52
rs17165909 7 93551606 GNG11 Silent INTRON 0.000131 5.91 4.06E−08 ~Infinity 9.49E−11 10.50
rs10841337 12 19897179 ? ? ? 3.73E−07 0.43 5.67E−06 0.68 9.49E−11 0.53
rs7217872 17 88988 RPH3AL, RPH3AL, Silent, Silent, INTRON 2.06E−05 0.46 7.59E−07 0.44 1.01E−10 0.45
RPH3AL, RPH3AL Silent, Silent
rs17638791 6 51940816 PKHD1, PKHD1 Silent, Silent INTRON 7.65E−05 3.02 1.63E−07 5.34 1.07E−10 3.67
rs10841322 12 19866642 ? ? ? 2.66E−07 0.42 1.04E−05 0.71 1.1E−10 0.52
kgp3933330 7 28583709 CREB5, CREB5, Silent, Silent, INTRON 4.2E−06 2.52 1.52E−06 2.41 1.16E−10 2.40
CREB5 Silent
kgp1005127 11 99881768 CNTN5, CNTN5, Silent, Silent, INTRON, EXON 0.000109 0.49 2.85E−07 0.34 1.25E−10 0.41
CNTN5, CNTN5 Silent, Silent
kgp6507761 7 319681 ? ? ? 0.000227 0.65 1.06E−07 0.49 1.25E−10 0.57
kgp7506434 1 13823114 LRRC38 Silent INTRON 4.04E−05 0.10 7.69E−07 0.08 1.26E−10 0.08
rs11022778 11 13390860 ARNTL, ARNTL, Silent, Silent, INTRON 1.4E−05 1.98 2.46E−06 1.70 1.26E−10 1.91
ARNTL Silent
kgp5908616 2 60329823 ? ? ? 0.0002 0.64 1.12E−07 0.46 1.27E−10 0.56
kgp12122821 6 51938210 PKHD1, PKHD1 Silent, Silent INTRON 7.65E−05 3.02 1.93E−07 5.16 1.29E−10 3.61
kgp10594414 1 216039833 USH2A Silent INTRON 1.05E−06 0.05 3.23E−06 0.26 1.31E−10 0.14
TABLE 27
Regression Analysis, Additive Model Corrected for rs1686004 + Log Relapse + EDSS (GALA, FORTE, Combined cohorts)
Gene GALA FORTE COMBINED
Posi- Loca- P- Odds P- Odds P- Odds
Name Chr tio Gene(s) Mutati tions(s value Rati value Rati value Rati
kgp8817856 6 32744440 HLA ? ? 2.41E−28 0.49 1.01E−19 0.32 7.56E−45 0.40
kgp3438641 5 98186154 ? ? ? 1.57E−29 4.50 9.08E−20 13.26 8.62E−45 5.49
kgp12113592 5 98160214 ? ? ? 2.60E−29 4.43 1.18E−19 13.10 1.06E−44 5.40
kgp3931548 5 98146468 ? ? ? 1.96E−29 4.42 9.08E−20 13.26 1.26E−44 5.39
rs727637 5 98213991 CHD1 Silent INTRON 1.96E−29 4.42 9.08E−20 13.26 1.26E−44 5.39
kgp1892256 5 98257441 CHD1 Silent INTRON 1.96E−29 4.42 9.08E−20 13.26 1.26E−44 5.39
kgp31017880 X 97136288 ? ? ? 3.74E−30 22.62 1.58E−17 Inf. 1.59E−44 31.18
kgp12230354 5 27037978 CDH9 Silent INTRON 1.36E−28 0.11 5.47E−19 0.09 1.60E−44 0.10
kgp3478190 8 69080975 PREX2 Silent INTRON 2.47E−29 2.14 2.07E−18 2.34 1.67E−44 2.22
kgp7903189 5 98229104 CHD1 Silent INTRON 1.71E−29 3.60 8.77E−20 13.26 2.01E−44 4.68
rs11956636 5 98159347 ? ? ? 2.82E−29 4.27 9.46E−20 13.27 2.81E−44 5.21
kgp11841858 5 98284488 ? ? ? 1.46E−29 3.84 1.83E−18 7.04 4.78E−44 4.38
kgp409852 5 98142161 ? ? ? 1.96E−29 4.42 6.53E−19 7.99 5.38E−44 4.73
rs1434781 8 69066793 PREX2 Silent INTRON 4.93E−29 2.05 3.59E−18 2.21 6.24E−44 2.12
rs2143466 6 32309323 C6orf10 Silent INTRON 1.87E−29 2.13 1.04E−17 1.95 6.35E−44 2.12
rs454748 6 32213210 ? ? ? 6.95E−30 2.24 1.19E−17 1.87 6.51E−44 2.10
rs2217788 8 69064811 PREX2 Silent INTRON 4.02E−29 2.08 4.53E−18 2.22 7.01E−44 2.14
rs2820263 6 1.05E+08 ? ? ? 2.80E−28 1.71 1.22E−19 2.75 7.49E−44 2.11
rs17166414 5 98202363 CHD1 Silent INTRON 4.48E−29 4.14 9.87E−19 9.98 8.17E−44 4.82
rs4713208 6 29283579 ? ? ? 6.45E−33 0.26 1.83E−16 1.11 8.43E−44 0.47
rs720831 6 29284518 ? ? ? 6.45E−33 0.26 1.83E−16 1.11 8.43E−44 0.47
kgp9832356 5 98262916 ? ? ? 4.48E−29 4.14 5.42E−19 10.27 9.52E−44 4.86
kgp5447044 6 26501768 BTN1A1 Silent INTRON 7.65E−29 0.33 7.91E−18 0.43 9.64E−44 0.36
rs2820259 6 1.05E+08 ? ? ? 2.31E−28 1.71 3.55E−19 2.54 9.66E−44 2.02
rs176901784 6 26555433 ? ? ? 4.13E−29 0.31 6.44E−18 0.42 1.12E−43 0.35
kgp4356222 5 98105883 RGMB, FL Silent, Sile INTRON, EXON 2.19E−29 4.75 2.36E−18 7.77 1.20E−43 5.03
rs4897704 8 1.35E+08 ? ? ? 3.72E−31 2.54 1.23E−17 1.89 1.23E−43 2.04
kgp4269732 5 98275939 ? ? ? 4.48E−29 4.14 6.76E−19 10.25 1.29E−43 4.86
kgp9938485 6 27021173 ? ? ? 9.70E−29 0.43 3.85E−17 0.57 1.45E−43 0.44
kgp6703510 5 98296594 ? ? ? 7.60E−29 3.91 5.36E−19 10.16 1.46E−43 4.73
kgp3203641 5 98245912 CHD1 Silent INTRON 4.48E−29 4.14 7.05E−15 10.23 1.54E−43 4.86
kgp11324749 8 69066259 PREX2 Silent INTRON 6.00E−29 2.04 4.09E−18 2.23 1.64E−43 2.12
rs7737398 5 97974536 ? ? ? 9.10E−30 5.46 8.14E−18 4.88 1.64E−43 4.77
indicates data missing or illegible when filed
Example 15 Selection of Genetic Markers Predictive of Response to Glatiramer Acetate Based on the analyses above, genetic markers were selected as Predictive of Response to Glatiramer Acetate based on the following p-value thresholds: Priority candidate variants: P<0.05 (combined cohorts); Priority Genes: Replicated P<0.05 In both cohorts; GWAS: P<10-4 (combined cohorts); and Placebo P<10-4 (placebo cohort).
The selected genetic markers are presented in Tables 28-31. Alleles associated with response are highlighted.
TABLE 28
Standard Response SNPs
Gala cohort Forte cohort
Minor Allele Minor Allele
Allele Freq. Allele Freq.
STANDARD PHENOTYPE Odds Freq. (Non- Odds Freq. (Non-
Major Minor P-value Ratio (Re- Re- P-value Ratio (Re- Re-
Prioritized Chromo- Posi- Allele Allele (Armitage (Minor spond- spond- (Armitage (Minor spond- spond-
Variants Name some tion Gene(s) (d) (D) Test) Allele) ers) ers) Test) Allele) ers) ers)
0 - Priority in kgp24415534 2 174156875 G A 3.40E−05 0.05 0.003 0.050 1.10E−02 0.14 0.005 0.033
Predictive
Model
kgp12008955 2 73759636 ALMS1 G A 9.26E−05 Zero 0.000 0.038 3.65E−04 0.12 0.007 0.057
kgp26026546 13 79972606 RBM26 A C 2.20E−04 Zero 0.000 0.034 4.46E−04 0.06 0.003 0.041
0 - Priority in rs16886004 7 78021500 MAGI2 A G 2.28E−03 2.15 0.199 0.110 3.25E−05 5.56 0.199 0.049
Predictive
Model
kgp25952891 13 80027089 A G 5.56E−04 Zero 0.000 0.029 4.30E−04 0.06 0.002 0.041
kgp3450875 16 57268931 RSPRY1 G A 6.63E−03 0.19 0.008 0.038 1.51E−05 0.07 0.005 0.066
rs10251797 7 78025427 MAGI2 C A 3.18E−03 2.07 0.199 0.113 4.05E−05 5.49 0.194 0.049
kgp2299673 20 16933074 G A 4.43E−03 0.26 0.015 0.054 4.23E−05 0.13 0.012 0.082
kgp10594414 1 216039833 USH2A A G 3.57E−05 0.05 0.003 0.050 1.25E−02 0.24 0.013 0.049
kgp1688752 21 43016736 G A 8.83E−04 0.34 0.045 0.113 1.48E−03 0.33 0.035 0.115
kgp12230354 5 27037978 CDH9 A C 3.70E−03 0.21 0.010 0.046 3.31E−05 0.14 0.015 0.090
rs543122 3 124165156 KALRN G A 4.73E−05 0.50 0.407 0.571 1.39E−02 0.59 0.439 0.566
kgp6236949 2 60301030 A G 6.37E−04 0.56 0.306 0.442 7.57E−03 0.55 0.261 0.385
kgp9627338 17 90155 RPH3AL A G 5.01E−04 0.47 0.104 0.208 3.13E−03 0.43 0.105 0.205
kgp11141512 20 35283733 NDRG3 G A 3.33E−03 0.30 0.020 0.067 3.65E−04 0.12 0.007 0.057
rs9579566 13 30980265 G A 2.08E−04 0.23 0.020 0.083 9.90E−03 0.30 0.025 0.074
rs2816838 10 52714759 G A 1.94E−03 0.51 0.139 0.233 1.80E−03 0.42 0.112 0.221
kgp4705854 12 19907696 G A 5.01E−05 0.51 0.303 0.467 2.87E−02 0.63 0.326 0.434
rs9817308 3 124182136 KALRN A C 2.85E−05 0.49 0.406 0.576 2.64E−02 0.62 0.453 0.566
0 - Priority in kgp8817856 6 32744440 G A 6.02E−04 0.53 0.364 0.492 3.73E−04 0.46 0.419 0.598
Predictive
Model
0 - Priority in kgp6214351 11 75546691 UVRAG A G 3.98E−03 0.42 0.051 0.113 2.65E−04 0.26 0.043 0.131
Predictive
Model
kgp2356388 16 119771577 IQCK G A 3.88E−04 0.43 0.121 0.221 1.94E−03 0.45 0.144 0.262
kgp7416024 9 21453902 G A 2.14E−03 0.13 0.005 0.038 3.81E−04 0.12 0.008 0.057
rs6718758 2 60528802 C A 5.70E−03 0.63 0.333 0.446 5.96E−04 0.47 0.281 0.443
rs7579987 2 60307009 G C 6.99E−03 0.64 0.356 0.466 3.91E−04 0.45 0.306 0.475
rs7217872 17 88988 RPH3AL G A 1.03E−03 0.49 0.106 0.204 2.42E−03 0.42 0.109 0.213
rs13394010 2 60302746 A G 7.74E−03 0.64 0.354 0.462 3.91E−04 0.45 0.306 0.475
rs7191155 16 19800213 IQCK A G 5.38E−04 0.44 0.121 0.218 1.93E−03 0.45 0.144 0.262
rs9931167 16 19792598 IQCK G A 5.38E−04 0.44 0.121 0.218 1.94E−03 0.45 0.144 0.262
rs11691553 2 60303554 C A 8.54E−03 0.65 0.355 0.463 3.72E−04 0.45 0.305 0.475
rs11648129 16 19820694 IQCK A G 6.54E−04 0.45 0.121 0.217 1.64E−03 0.44 0.143 0.262
kgp25216186 1 23758427 ASAP3 A G 1.32E−03 0.07 0.003 0.033 2.45E−03 0.07 0.002 0.033
kgp29794723 10 18397332 A G 4.77E−03 0.31 0.023 0.067 3.54E−04 0.18 0.018 0.082
rs3829539 16 19722366 C16orf88 A G 5.38E−04 0.44 0.121 0.218 2.10E−03 0.45 0.145 0.262
rs6895094 5 141037277 ARAP3 A C 6.58E−04 0.56 0.384 0.521 1.19E−02 0.60 0.353 0.484
kgp1009249 12 19838534 G A 1.74E−04 0.48 0.179 0.307 1.03E−02 0.54 0.211 0.320
rs10203396 2 60305110 A G 8.67E−03 0.65 0.356 0.463 4.43E−04 0.46 0.308 0.475
kgp3854160 16 19721806 C16orf88 G A 6.54E−04 0.45 0.121 0.217 1.94E−03 0.45 0.144 0.262
rs6497396 16 19735697 IQCK A G 1.30E−03 0.48 0.131 0.225 7.65E−04 0.43 0.155 0.287
rs13419758 2 60302920 G A 8.67E−03 0.65 0.356 0.463 5.22E−04 0.47 0.308 0.475
rs8055485 16 19750051 IQCK A G 6.54E−04 0.45 0.121 0.217 2.10E−03 0.45 0.145 0.262
rs9931211 16 19813605 IQCK A G 6.54E−04 0.45 0.121 0.217 2.10E−03 0.45 0.145 0.262
kgp5869992 12 49219569 CACNB3 A G 3.71E−04 0.57 0.389 0.542 2.00E−02 0.62 0.379 0.500
kgp9320791 2 60309952 C G 8.67E−03 0.65 0.356 0.463 5.27E−04 0.46 0.310 0.475
kgp7730397 16 19740243 IQCK A G 1.09E−03 0.47 0.126 0.218 1.64E−03 0.44 0.143 0.262
kgp11002881 11 118219897 CD3G A G 4.98E−03 0.14 0.005 0.034 4.46E−04 0.06 0.003 0.041
kgp3205849 10 121531725 INPP5F A G 8.42E−05 0.48 0.172 0.312 5.88E−02 0.63 0.183 0.262
kgp6127371 4 153856357 A G 3.69E−04 0.16 0.013 0.063 9.38E−03 0.28 0.020 0.066
kgp10305127 11 99881768 CNTN5 A G 4.21E−03 0.51 0.101 0.182 2.60E−03 0.39 0.068 0.156
rs6535882 4 153848128 G A 3.83E−04 0.18 0.013 0.063 9.06E−03 0.27 0.020 0.066
kgp6700691 4 153849531 A G 3.83E−04 0.18 0.013 0.063 9.06E−03 0.27 0.020 0.066
rs11029892 11 27269546 G A 1.72E−03 1.83 0.343 0.229 3.44E−03 2.08 0.358 0.221
kgp270001 16 19750275 IQCK G A 1.08E−03 0.48 0.131 0.227 1.44E−03 0.45 0.154 0.279
kgp8192546 12 19903173 G A 6.52E−05 0.47 0.215 0.358 2.64E−02 0.62 0.256 0.361
kgp5068397 16 19756348 IQCK A G 7.59E−04 0.50 0.164 0.273 1.56E−03 0.47 0.203 0.336
kgp10910719 16 19803199 IQCK C A 9.01E−04 0.46 0.121 0.214 1.94E−03 0.45 0.144 0.262
kgp2959751 6 58719342 G A 9.81E−04 0.22 0.015 0.063 7.48E−03 0.24 0.015 0.057
rs950928 16 19824638 IQCK A G 6.59E−04 0.45 0.126 0.223 3.11E−03 0.46 0.149 0.262
rs1858973 16 19743649 IQCK A G 6.54E−04 0.45 0.121 0.217 2.67E−03 0.46 0.148 0.262
rs2660214 10 52732452 A G 3.98E−03 0.54 0.141 0.229 2.37E−03 0.43 0.114 0.221
kgp2709692 18 3000808 LPIN2 C A 2.36E−03 0.27 0.020 0.067 5.25E−03 0.19 0.010 0.049
kgp11210903 22 30898906 SEC14L4 G A 3.70E−04 0.10 0.005 0.046 4.98E−02 0.19 0.005 0.025
kgp8030775 8 6328607 MCPHI A C 2.54E−04 0.36 0.018 0.050 1.69E−05 0.07 0.005 0.066
rs10841337 12 19897179 A G 4.26E−05 0.47 0.217 0.367 4.27E−02 0.64 0.265 0.361
kgp8178358 14 70923024 ADAM21 A G 3.36E−03 0.08 0.003 0.029 3.81E−04 0.12 0.008 0.057
kgp11843177 11 27316568 A G 1.95E−03 1.85 0.321 0.210 4.13E−03 2.07 0.338 0.205
kgp23737989 7 97217288 G A 3.27E−03 0.08 0.003 0.029 1.57E−03 Zero 0.000 0.025
rs7187976 16 19708196 C16orf62 A G 1.08E−03 0.48 0.131 0.227 1.83E−03 0.45 0.157 0.278
rs17577980 6 32359821 HCG23 G A 2.33E−04 2.36 0.228 0.106 5.31E−03 2.94 0.164 0.067
kgp5908616 2 60329823 A C 8.71E−03 0.65 0.346 0.454 1.05E−03 0.48 0.295 0.451
kgp26995430 3 53359406 DCP1A G A 3.40E−05 0.65 0.003 0.050 2.14E−01 0.39 0.010 0.025
kgp6996560 13 110124242 G A 7.81E−03 0.23 0.010 0.042 4.30E−04 0.06 0.002 0.041
rs4782279 16 19759007 IQCK A C 1.26E−03 0.49 0.136 0.233 1.99E−03 0.46 0.158 0.279
rs8053136 16 19767129 IQCK A C 1.27E−03 0.53 0.179 0.288 1.68E−03 0.47 0.210 0.344
kgp11328629 10 120711084 G A 2.03E−03 2.62 0.134 0.058 3.11E−03 3.81 0.140 0.041
kgp8200264 10 12858372 CAMKID A G 8.64E−04 0.26 0.020 0.076 3.36E−03 0.31 0.033 0.098
kgp6835138 20 40712994 PTPRT G A 6.20E−05 0.08 0.005 0.054 1.26E−01 0.36 0.012 0.033
kgp841428 5 141036337 ARAP3 A G 9.84E−04 0.57 0.384 0.517 1.52E−02 0.61 0.358 0.484
rs3815822 16 29872361 CDIPT A G 3.18E−03 1.62 0.490 0.367 4.87E−03 1.83 0.527 0.385
rs1579771 3 157278882 C3orf55 A C 3.35E−04 2.02 0.376 0.246 1.64E−02 1.81 0.356 0.246
kgp4734301 11 27315427 A G 2.36E−03 1.83 0.321 0.213 4.13E−03 2.07 0.338 0.205
rs11029928 11 27319188 G A 2.36E−03 1.83 0.321 0.213 4.13E−03 2.07 0.338 0.205
rs10941322 12 19866642 G A 3.20E−05 0.46 0.217 0.367 9.47E−02 0.69 0.251 0.328
kgp1786079 7 144701118 A G 5.35E−04 0.48 0.106 0.213 9.86E−03 0.49 0.130 0.221
kgp5053636 2 205356730 C A 1.01E−02 0.32 0.020 0.058 1.02E−04 0.22 0.028 0.115
kgp9601342 9 18959317 FAM154A G A 4.29E−03 0.40 0.038 0.097 2.94E−03 0.26 0.025 0.083
kgp8183049 13 40634155 G A 5.58E−04 Zero 0.000 0.029 6.90E−02 Zero 0.000 0.008
kgp5564995 6 26414060 BTN3A1 C A 1.56E−04 1.35 0.153 0.057 3.98E−02 2.30 0.137 0.070
kgp27500525 9 30278677 A G 3.79E−03 Zero 0.000 0.021 1.57E−03 Zero 0.000 0.025
rs11022778 11 13390860 ARNTL A C 4.49E−04 1.96 0.336 0.204 4.87E−02 1.58 0.366 0.270
kgp10826273 2 176163817 G A 5.89E−04 Zero 0.000 0.029 6.96E−02 Zero 0.000 0.008
rs2494712 3 116796116 A G 1.36E−02 1.74 0.220 0.142 1.24E−03 2.54 0.274 0.131
kgp1779154 12 73686930 A G 3.12E−03 0.08 0.003 0.029 2.45E−03 0.07 0.002 0.033
kgp6190988 5 10699522 DAP G A 3.27E−03 0.08 0.003 0.029 2.22E−03 0.07 0.002 0.033
kgp6507761 7 319681 A G 8.94E−03 0.65 0.457 0.567 2.00E−03 0.54 0.400 0.566
rs2074037 16 19725130 C16orf88 G A 1.49E−03 0.47 0.126 0.216 2.46E−03 0.46 0.147 0.262
rs4143493 6 51829939 PKHD1 G A 8.85E−03 3.00 0.078 0.029 1.57E−03 7.56 0.102 0.016
kgp1699628 6 18032535 A G 1.73E−04 0.51 0.437 0.585 2.99E−02 0.63 0.470 0.582
rs7024953 9 18960334 FAM154A A G 4.68E−03 0.40 0.038 0.096 3.41E−03 0.27 0.025 0.082
kgp10974833 13 77319132 A G 3.27E−03 0.08 0.003 0.029 2.59E−03 0.07 0.003 0.033
kgp10412303 2 205303530 G A 1.21E−02 0.37 0.413 0.067 1.73E−04 0.21 0.027 0.107
kgp9669946 17 63733872 NOL11 A G 1.28E−03 0.51 0.154 0.256 3.31E−03 0.50 0.179 0.303
rs17224858 3 124105297 KALRN G A 3.71E−05 0.45 0.172 0.313 1.22E−01 0.69 0.204 0.270
rs6840089 4 153713220 ARFIP1 G A 8.57E−04 0.20 0.013 0.058 9.06E−03 0.27 0.020 0.066
rs7666442 4 153753101 ARFIP1 A G 8.57E−04 0.20 0.013 0.058 9.06E−03 0.27 0.020 0.066
rs7672014 4 153818501 ARFIP1 G A 8.57E−04 0.20 0.013 0.058 9.06E−03 0.27 0.020 0.066
rs7677801 4 153795067 ARFIP1 A G 8.68E−04 0.20 0.013 0.059 9.38E−03 0.28 0.020 0.066
rs4669694 2 11263948 FLJ33534 G A 1.85E−03 0.48 0.094 0.182 1.43E−02 0.46 0.083 0.156
kgp10523170 16 5221617 G A 2.00E−02 0.12 0.003 0.021 9.95E−05 0.05 0.002 0.057
kgp5216209 3 170740453 SLC2A2 C A 1.75E−03 0.21 0.013 0.055 4.56E−03 0.24 0.017 0.066
rs720176 16 19721515 C16orf88 A G 1.77E−03 0.48 0.128 0.217 2.67E−03 0.46 0.148 0.262
kgp7481870 16 19729016 C16orf88, G C 5.94E−04 0.45 0.133 0.231 8.16E−03 0.50 0.160 0.262
IQCK
rs1532365 12 49204421 G A 1.90E−03 0.61 0.356 0.487 1.26E−02 0.28 0.334 0.459
rs12943140 17 65718771 NOL11 G A 1.42E−03 0.51 0.155 0.256 3.47E−03 0.50 0.179 0.303
kgp11702474 4 153712868 ARFIP1 A G 8.97E−04 0.20 0.013 0.058 9.38E−03 0.28 0.020 0.066
rs10498793 6 31139707 PKHD1 G A 8.85E−03 3.00 0.078 0.029 1.94E−03 7.33 0.100 0.016
kgp6539666 3 157292022 C3orf55 A G 9.41E−04 1.94 0.354 0.238 1.61E−02 1.83 0.354 0.246
kgp10679353 16 19800133 IQCK G A 1.51E−03 0.49 0.129 0.221 2.30E−03 0.46 0.159 0.279
kgp9410843 10 121484477 A G 2.25E−04 0.50 0.173 0.304 6.76E−02 0.64 0.186 0.262
kgp6772915 9 18978739 FAM154A A C 8.72E−03 0.42 0.041 0.093 1.83E−03 0.24 0.023 0.082
kgp20478926 8 21050249 A G 1.67E−03 0.38 0.023 0.092 2.91E−03 0.44 0.038 0.133
kgp10619195 4 99417717 TSPAN5 A G 2.87E−04 0.28 0.035 0.104 3.30E−02 0.46 0.045 0.098
rs1544352 16 19713183 A G 2.28E−03 0.50 0.132 0.221 2.15E−03 0.45 0.153 0.270
kgp15390522 1 205017963 CNTN2 G A 2.14E−03 0.13 0.005 0.038 1.37E−03 0.10 0.002 0.025
kgp24727706 22 49286357 LOC100128946 G A 1.13E−03 0.24 0.018 0.067 4.15E−02 0.29 0.012 0.041
rs931570 12 49195124 G A 2.42E−03 0.61 0.356 0.483 1.11E−02 0.59 0.332 0.459
kgp10591989 17 65697118 A G 1.60E−03 0.48 0.111 0.200 9.17E−03 0.50 0.110 0.205
kgp12557319 6 8794609 A G 2.04E−02 0.12 0.003 0.021 8.27E−05 0.08 0.005 0.057
kgp345301 16 19730354 IQCK A C 2.05E−03 0.48 0.122 0.209 2.28E−03 0.45 0.146 0.262
kgp8615910 5 30927198 A T 1.47E−04 0.42 0.111 0.221 5.56E−02 0.59 0.135 0.205
kgp2245775 13 91402506 G A 2.67E−02 0.66 0.258 0.338 8.86E−04 0.43 0.185 0.320
kgp29367521 4 134471944 G A 4.84E−03 0.14 0.005 0.034 2.02E−03 0.11 0.005 0.042
kgp7506434 1 13823114 LRRC38 A G 5.24E−03 0.14 0.005 0.033 2.36E−03 0.09 0.002 0.041
rs4780822 16 19727993 C16orf88, A G 2.32E−03 0.50 0.129 0.217 1.71E−03 0.45 0.156 0.279
IQCK
kgp512180 16 10829457 G A 2.02E−03 0.57 0.235 0.349 9.63E−03 0.55 0.239 0.344
rs1604169 5 84213343 A C 1.45E−02 0.66 0.386 0.483 2.13E−03 0.50 0.323 0.467
kgp25921291 13 78418857 G A 2.49E−03 0.18 0.008 0.046 7.68E−03 0.17 0.007 0.041
rs16901784 6 26553433 C A 1.57E−03 0.45 0.073 0.154 2.10E−03 0.43 0.105 0.213
kgp6228750 1 110261382 A G 1.92E−02 0.44 0.040 0.083 3.30E−04 0.26 0.030 0.115
kgp9354820 15 93793636 G A 2.86E−04 0.06 0.003 0.046 1.17E−01 0.29 0.007 0.025
kgp8106690 12 128734969 A G 2.00E−02 0.61 0.141 0.213 2.38E−04 0.40 0.128 0.270
kgp5144181 2 30364733 G A 3.79E−02 0.49 0.040 0.079 8.32E−05 0.16 0.017 0.090
kgp9627406 9 132997137 NCS1 G A 9.94E−04 0.39 0.070 0.163 2.89E−01 0.58 0.030 0.050
kgp2262166 9 18960391 FAM154A A C 4.45E−03 0.40 0.038 0.096 5.93E−03 0.30 0.027 0.082
kgp4223880 2 10584122 ODC1 A G 4.99E−04 0.06 0.003 0.038 3.23E−02 0.22 0.008 0.033
kgp61811 1 160346794 A C 5.90E−03 0.20 0.008 0.042 2.45E−03 0.07 0.002 0.033
kgp9421884 19 11049860 G A 9.65E−02 0.56 0.048 0.079 3.73E−06 0.24 0.047 0.180
rs8050872 16 19803846 IQCK G A 1.99E−03 0.51 0.136 0.229 2.88E−03 0.47 0.162 0.279
rs7864679 9 18945161 FAM154A G A 1.69E−02 0.48 0.046 0.096 7.87E−04 0.21 0.020 0.082
kgp2446153 5 152980439 GR1A1 G A 5.31E−04 0.06 0.003 0.038 3.17E−02 0.22 0.007 0.033
kgp7804623 1 41125455 RIMS3 G A 2.90E−04 1.99 0.346 0.208 5.88E−02 1.57 0.336 0.246
rs3792135 2 100062163 REV1 A G 5.97E−04 0.48 0.120 0.227 3.49E−02 0.55 0.131 0.205
rs8035826 15 94832144 C A 4.54E−03 1.59 0.465 0.345 1.05E−02 1.76 0.513 0.385
kgp85534 2 14374582 G A 2.11E−04 0.13 0.008 0.055 1.26E−01 0.36 0.012 0.033
rs11192461 10 107266483 G A 7.86E−03 0.49 0.081 0.146 7.33E−04 0.38 0.087 0.197
kgp297178 9 18942615 FAM154A G A 2.48E−02 0.48 0.043 0.088 3.36E−04 0.18 0.017 0.082
kgp2045074 6 51187450 C A 4.02E−04 0.10 0.005 0.046 2.05E−01 0.30 0.005 0.016
rs10049206 3 157211691 G A 5.70E−04 1.97 0.369 0.246 2.77E−02 1.71 0.356 0.254
rs9834010 3 137216222 C A 5.70E−04 1.97 0.369 0.246 2.77E−02 1.71 0.356 0.254
kgp971582 6 51911703 PKHD1 A G 4.96E−03 2.99 0.091 0.033 4.76E−03 4.89 0.104 0.025
kgp22791211 X 92601376 G A 2.20E−03 0.65 0.391 0.538 8.20E−03 0.61 0.396 0.550
kgp4573213 3 124199924 KALRN A G 5.14E−05 0.45 0.174 0.313 1.43E−01 0.71 0.208 0.270
kgp19568724 14 21486590 NDRG2 G A 1.32E−03 0.07 0.003 0.033 5.09E−03 0.19 0.010 0.049
kgp9071686 9 21419161 G A 1.19E−02 0.16 0.005 0.029 3.65E−04 0.12 0.007 0.057
kgp652534 4 13612731 BODIL C G 2.84E−01 0.45 0.008 0.017 4.64E−07 0.05 0.005 0.082
kgp1224440 1 247199991 A C 3.76E−03 0.52 0.096 0.179 1.21E−03 0.41 0.122 0.238
kgp2465184 9 18942204 FAM154A A C 2.48E−02 0.41 0.043 0.088 3.54E−04 0.18 0.018 0.082
kgp11543962 10 109379303 G A 1.42E−02 0.21 0.008 0.034 3.81E−04 0.12 0.008 0.057
kgp4543470 2 213359411 A C 3.80E−06 0.36 0.106 0.246 4.45E−01 0.80 0.161 0.189
kgp5579170 17 65681762 PITPNC1 G A 2.00E−03 0.44 0.076 0.151 3.74E−03 0.45 0.093 0.192
kgp4812831 6 51910905 PKHD1 A G 4.96E−03 2.99 0.091 0.033 4.61E−03 4.95 0.102 0.025
rs2598360 9 114133899 KIAA0368 G A 4.06E−03 0.61 0.386 0.500 7.26E−03 0.58 0.361 0.500
kgp10633631 8 17504188 MTUS1 A G 9.73E−03 Zero 0.000 0.017 5.52E−04 Zero 0.000 0.041
kgp3651787 16 84992155 G A 6.93E−02 0.19 0.008 0.025 1.43E−05 0.09 0.007 0.074
rs823829 9 114105079 A C 1.84E−03 0.58 0.407 0.529 1.58E−02 0.61 0.391 0.516
kgp279772 8 2105376 T A 6.51E−03 0.61 0.237 0.338 8.63E−04 0.47 0.256 0.410
kgp20163979 8 79366479 A C 2.33E−04 Zero 0.000 0.033 3.69E−01 0.30 0.002 0.008
kgp21171930 4 80362934 A G 3.79E−03 Zero 0.000 0.021 2.45E−03 0.07 0.002 0.013
kgp2092817 5 39632583 G A 8.09E−03 0.10 0.003 0.025 1.57E−03 Zero 0.000 0.025
kgp3598409 13 31632449 GLDN G A 5.89E−04 Zero 0.000 0.029 7.37E−02 0.15 0.002 0.016
kgp6469620 1 41233946 NFYC G A 1.54E−03 1.75 0.401 0.275 2.30E−02 1.66 0.418 0.303
rs3818675 10 12838045 CAMKID G A 1.81E−03 0.28 0.020 0.071 5.56E−03 0.32 0.030 0.090
kgp9530088 11 30501034 MPPED2 A G 4.45E−02 0.70 0.276 0.350 2.34E−04 0.44 0.221 0.392
rs2453478 12 49302743 A G 1.81E−03 0.61 0.356 0.488 1.98E−02 0.62 0.341 0.459
kgp10558725 18 3070717 MYOM1 G A 7.81E−03 0.23 0.010 0.042 1.79E−03 0.14 0.008 0.049
kgp28586329 8 6304848 MCPH1 A G 8.09E−03 0.10 0.003 0.025 1.61E−03 Zero 0.000 0.025
kgp30282494 5 72863824 UTP15 A G 3.27E−03 0.08 0.003 0.029 1.02E−02 Zero 0.000 0.016
rs7524848 1 41106774 RIMS3 A C 1.68E−04 2.05 0.351 0.208 9.59E−02 1.48 0.333 0.254
kgp9806386 5 138068034 A C 5.89E−04 Zero 0.000 0.029 7.57E−02 0.15 0.003 0.016
kgp4137859 6 32434481 A G 4.49E−04 2.42 0.205 0.100 1.43E−02 2.53 0.155 0.074
kgp1753445 21 39811162 ERG G A 7.36E−03 2.09 0.162 0.092 2.76E−03 3.12 0.177 0.067
kgp9354462 2 149894403 A C 2.89E−03 0.61 0.305 0.425 1.18E−02 0.58 0.290 0.410
kgp26533576 6 99139641 A C 2.40E−04 0.13 0.008 0.054 3.78E−01 0.45 0.008 0.016
kgp2023214 16 76293345 A G 5.03E−03 0.52 0.083 0.163 4.31E−03 0.45 0.078 0.172
kgp6768546 4 133864174 FHDC1 G A 1.95E−03 0.23 0.015 0.059 9.06E−03 0.27 0.020 0.066
kgp1098237 9 114173681 KIAA0368 G A 3.51E−03 0.61 0.379 0.496 9.79E−03 0.59 0.358 0.492
kgp4559907 6 133253232 G A 4.08E−04 0.56 0.311 0.454 3.11E−02 0.63 0.352 0.459
rs1644418 10 12838409 CAMKID A G 1.77E−03 0.26 0.018 0.067 5.33E−03 0.32 0.030 0.090
kgp11804835 6 32396146 C A 8.85E−04 2.34 0.190 0.092 9.90E−03 2.77 0.150 0.066
rs7029123 9 114136169 KIAA0368 A G 6.13E−03 0.63 0.391 0.500 6.39E−03 0.57 0.358 0.500
kgp2688306 7 28560259 CREB5 A G 1.51E−03 2.84 0.126 0.050 1.23E−02 3.21 0.118 0.041
kgp2618591 8 108994382 RSPO2 G A 1.11E−03 0.32 0.035 0.096 1.32E−02 0.39 0.047 0.107
rs2845371 22 17178213 G A 5.95E−03 1.59 0.467 0.353 9.08E−03 1.78 0.508 0.377
kgp5409955 9 18980841 FAM154A G A 2.34E−03 0.35 0.033 0.092 2.86E−02 0.35 0.025 0.066
rs7228827 18 76900411 ATP9B G A 6.4E−04 2.27 0.215 0.108 2.61E−02 1.98 0.198 0.107
kgp1912531 2 137850215 TH5D7B A G 4.12E−03 2.00 0.192 0.104 9.55E−03 2.22 0.215 0.107
kgp4162414 6 51868165 PKHD1 G A 6.71E−03 2.89 0.088 0.033 4.61E−03 4.95 0.102 0.025
rs2926455 10 107260501 A G 8.73E−03 0.50 0.083 0.148 1.03E−03 0.39 0.090 0.197
kgp1669685 7 78028723 MAGI2 A C 5.48E−03 1.80 0.254 0.160 3.26E−03 2.40 0.254 0.131
kgp7059449 2 41255455 A C 3.03E−02 2.89 0.056 0.021 1.57E−03 12.79 0.092 0.008
rs3899755 X 68447361 C A 7.42E−05 2.48 0.227 0.088 1.92E−01 1.42 0.204 0.148
rs2309760 4 183591133 ODZ3 A G 1.87E−03 0.61 0.369 0.500 5.20E−02 0.67 0.320 0.418
kgp2788291 18 45153979 G A 9.15E−03 0.57 0.119 0.197 1.21E−03 0.41 0.122 0.238
kgp3933330 7 28563709 CREB5 A G 4.00E−04 2.42 0.198 0.088 3.21E−02 2.15 0.158 0.082
rs7062312 X 68447052 G A 7.68E−05 2.49 0.226 0.088 1.92E−001 1.42 0.204 0.148
kgp337461 6 125019969 NKAIN2 A G 2.96E−02 0.61 0.126 0.189 1.84E−04 0.39 0.119 0.362
rs6899068 5 126591501 G A 6.36E−03 1.60 0.414 0.304 1.48E−03 2.19 0.396 0.246
kgp8046214 4 153726582 ARFIP1 A G 8.57E−04 0.20 0.013 0.058 2.48E−03 0.31 0.020 0.058
rs6835202 4 153855186 C A 1.75E−03 0.21 0.013 0.055 9.06E−03 0.27 0.020 0.066
kgp10620244 8 133472755 KCNQ3 G A 1.29E−03 2.11 0.220 0.117 2.23E−02 1.96 0.219 0.123
kgp11407560 2 65096583 A G 2.01E−04 0.25 0.025 0.092 3.43E−01 0.59 0.025 0.041
rs3799383 6 26510748 G A 1.90E−03 0.45 0.071 0.150 2.58E−03 0.44 0.107 0.213
rs6845927 4 153799603 ARFIP1 A C 2.20E−03 0.24 0.015 0.058 9.38E−03 0.28 0.020 0.066
rs10489312 1 175526526 TNR A G 1.28E−03 0.50 0.121 0.221 1.88E−02 0.53 0.135 0.221
kgp11633966 11 37701793 G A 3.96E−03 0.56 0.172 0.267 2.75E−03 0.57 0.129 0.213
rs7496451 15 25718875 G A 8.50E−03 1.82 0.220 0.138 6.16E−03 2.18 0.259 0.139
kgp1048169 4 78109591 G A 5.55E−04 0.46 0.106 0.208 7.04E−02 0.60 0.109 0.172
kgp8990121 9 27215039 TEK C A 1.08E−03 2.57 0.157 0.071 3.93E−02 1.96 0.177 0.098
kgp26528455 6 72737785 RIMS1 G A 2.26E−03 0.26 0.018 0.063 1.23E−02 0.32 0.017 0.066
kgp4755147 2 149894654 A C 2.91E−03 0.61 0.308 0.429 1.57E−02 0.59 0.294 0.410
kgp10372946 10 113980657 JAKMIP3 G A 1.26E−03 13.37 0.051 0.004 2.45E−02 7.37 0.055 0.008
rs1380706 2 57864042 A G 2.87E−03 1.68 0.393 0.271 2.34E−02 1.67 0.424 0.311
kgp12182745 8 125465203 TRMT12 A T 1.17E−03 0.41 0.054 0.133 8.88E−02 0.53 0.041 0.083
kgp3951463 3 157280172 C3orf55 C A 1.42E−03 1.87 0.348 0.253 2.46E−02 1.75 0.348 0.246
kgp8602316 7 335911 G A 8.14E−03 1.59 0.393 0.288 6.93E−03 1.77 0.440 0.295
rs16927077 11 10620629 MRVII-AS1 G A 5.86E−03 0.53 0.106 0.183 4.35E−02 0.48 0.055 0.107
kgp6959492 4 153687676 A G 1.89E−03 0.21 0.013 0.054 9.06E−03 0.27 0.020 0.066
kgp8793915 11 109012665 A G 1.42E−03 Zero 0.000 0.025 6.90E−02 Zero 0.000 0.008
kgp13161760 21 18192806 G A 3.27E−03 0.08 0.003 0.029 1.45E−02 Zero 0.000 0.025
kgp6567154 4 3442146 G C 9.31E−03 0.64 0.274 0.375 1.61E−03 0.51 0.274 0.426
kgp2282938 22 32719612 G A 1.70E−02 0.28 0.013 0.042 2.96E−04 0.18 0.018 0.083
kgp355723 8 75370402 GDAPI A G 2.94E−01 0.19 0.005 0.013 1.13E−06 Zero 0.000 0.057
rs10201643 2 149906641 LYPD6B C A 3.22E−03 0.62 0.308 0.429 1.51E−02 0.59 0.294 0.410
kgp27640141 12 118805689 TAOK3 G A 2.02E−02 0.14 0.003 0.025 2.54E−04 Zero 0.000 0.033
rs7670525 4 153814538 ARFIP1 A G 1.97E−03 0.21 0.013 0.054 9.06E−03 0.27 0.020 0.066
kgp28817122 8 122487115 A G 9.13E−03 0.28 0.015 0.050 1.34E−03 0.21 0.018 0.074
kgp5014707 9 1702186 G A 2.54E−02 Zero 0.000 0.013 2.54E−04 Zero 0.000 0.033
kgp7092772 14 22379841 G A 9.73E−03 Zero 0.000 0.017 1.57E−03 Zero 0.000 0.025
kgp3477351 19 295864 G A 2.54E−02 Zero 0.000 0.013 2.54E−04 Zero 0.000 0.033
kgp23298674 21 20962564 C A 1.49E−03 Zero 0.000 0.025 6.90E−02 Zero 0.000 0.008
kgp12083934 16 10128979 A G 3.15E−03 0.58 0.233 0.343 1.13E−02 0.56 0.230 0.344
kgp485316 7 15372018 AGMO G A 8.50E−05 1.93 0.490 0.325 1.49E−01 1.36 0.443 0.369
kgp25191871 1 115687027 A C 6.93E−03 0.38 0.030 0.081 5.66E−03 0.27 0.023 0.074
kgp24131116 2 213906695 IKZF2 G A 9.91E−03 Zero 0.000 0.017 1.57E−03 Zero 0.000 0.025
kgp9854133 3 31334098 G A 6.08E−04 Zero 0.000 0.029 ? Zero 0.000 0.000
kgp228119I8 X 21960214 SMS C A 4.90E−03 0.52 0.063 0.142 1.38E−02 0.45 0.047 0.115
kgp7792268 13 23070499 C A 6.43E−04 0.18 0.010 0.058 7.70E−02 0.35 0.015 0.041
kgp11316379 11 9814612 LOC283104, G A 1.37E−02 0.66 0.353 0.457 1.59E−03 0.41 0.336 0.483
SBF2
kgp27571222 12 56243724 A G 9.10E−03 0.11 0.003 0.029 1.65E−03 Zero 0.000 0.025
rs1986214 13 42948531 A G 4.17E−03 1.79 0.272 0.171 1.06E−02 1.99 0.285 0.172
kgp1054273 12 67131774 G A 2.33E−04 Zero 0.000 0.033 2.03E−01 0.30 0.005 0.016
kgp9551947 18 42502140 SETBP1 G A 3.78E−03 Zero 0.000 0.021 2.25E−03 0.11 0.005 0.041
kgp5483926 3 144352913 A C 6.84E−02 Zero 0.000 0.008 1.51E−05 0.07 0.005 0.066
kgp4155998 1 184734012 G A 2.76E−02 0.19 0.005 0.025 2.54E−04 Zero 0.000 0.033
kgp2958113 5 163341388 A C 2.76E−02 0.19 0.005 0.025 2.54E−04 Zero 0.000 0.033
kgp8335513 11 4926211 G A 8.09E−03 0.10 0.003 0.025 2.45E−03 0.07 0.002 0.033
kgp5388938 8 79087167 G A 9.26E−05 Zero 0.000 0.038 6.79E−01 0.60 0.005 0.008
kgp28687699 8 73225285 C A 9.26E−05 Zero 0.000 0.038 6.79E−01 0.60 0.005 0.008
kgp11627530 14 78954642 NRXN3 A G 2.83E−03 0.41 0.048 0.113 3.48E−03 0.40 0.070 0.156
kgp24753470 1 26013940 MANIC1 A C 1.19E−02 0.16 0.005 0.029 1.61E−03 Zero 0.000 0.025
kgp1285441 3 56931141 ARHGEF3 G A 8.54E−04 0.49 0.124 0.225 3.75E−02 0.57 0.137 0.213
rs17638791 6 51940816 PKHD1 A G 7.32E−03 2.73 0.093 0.038 4.61E−03 4.95 0.102 0.025
rs2325911 6 125027223 NKAIN2 C A 3.65E−03 0.61 0.121 0.179 1.48E−04 0.39 0.118 0.262
kgp10967046 15 66174387 MEGF11 G A 5.49E−02 0.50 0.041 0.075 1.04E−04 0.24 0.030 0.123
rs12013377 X 92620062 A G 5.41E−03 0.67 0.409 0.542 6.48E−03 0.60 0.400 0.557
kgp7186699 4 184878777 STOX2 G A 1.79E−02 2.38 0.088 0.038 1.13E−03 13.37 0.100 0.008
kgp9368119 7 11707419 THSD7A A G 1.06E−02 0.65 0.427 0.329 1.75E−02 0.60 0.343 0.459
kgp124162 11 72356846 PDE2A A G 1.89E−03 0.21 0.013 0.054 1.55E−02 0.28 0.018 0.057
kgp8440035 4 78058785 G A 6.77E−04 0.25 0.018 0.075 9.68E−02 0.43 0.020 0.049
rs4738738 8 59844254 TOX A C 1.63E−02 1.49 0.424 0.324 6.74E−04 2.22 0.425 0.254
kgp7802182 19 56759170 A G 2.53E−02 0.67 0.222 0.304 7.43E−04 0.44 0.194 0.336
kgp2923815 19 43931355 G A 3.62E−03 0.44 0.066 0.133 1.21E−02 0.42 0.063 0.131
rs3767955 1 41104475 RIMS3 G A 2.57E−04 2.00 0.351 0.213 1.04E−01 1.47 0.331 0.254
kgp3418770 10 59425598 A G 5.89E−03 6.24 0.048 0.008 6.50E−03 Infinity 0.056 0.000
rs17449018 9 7060825 KDM4C G A 3.68E−04 2.03 0.326 0.195 7.93E−02 1.53 0.311 0.230
kgp4524468 22 32724312 A G 1.99E−04 2.16 0.304 0.169 7.14E−02 1.62 0.259 0.178
kgp4418535 6 32431558 C A 5.99E−04 2.37 0.202 0.100 1.80E−02 2.46 0.152 0.074
kgp22823022 X 9742468 G A 7.11E−02 0.71 0.151 0.214 8.53E−05 0.41 0.115 0.280
kgp7063887 1 189928568 G A 8.17E−03 0.48 0.058 0.121 1.47E−02 0.36 0.030 0.082
rs1621509 7 2969680 CARD11 G A 2.25E−03 2.06 0.226 0.133 3.02E−02 1.82 0.253 0.158
kgp4842590 1 110249364 A C 2.30E−02 0.37 0.020 0.055 8.15E−04 0.17 0.010 0.066
rs11192469 10 107282331 A G 1.11E−02 0.51 0.081 0.143 1.30E−03 0.39 0.085 0.189
kgp8303520 7 154911234 C A 5.76E−03 0.63 0.449 0.563 3.00E−02 0.64 0.376 0.492
rs1345334 2 60324127 A G 1.42E−02 0.67 0.374 0.475 2.98E−03 0.52 0.341 0.484
rs9876830 3 157311299 C3orf55 G A 1.35E−03 1.89 0.351 0.238 2.85E−02 1.72 0.346 0.246
kgp11285862 21 18177980 A G 1.36E−03 0.07 0.003 0.033 4.46E−02 0.19 0.002 0.025
rs2824070 21 18205972 A G 3.48E−01 0.20 0.010 0.046 1.11E−02 0.24 0.010 0.049
kgp7181058 14 98363696 G A 2.11E−03 0.24 0.015 0.058 4.15E−02 0.29 0.012 0.041
kgp5002011 1 110265738 G A 3.87E−02 0.46 0.035 0.071 2.96E−04 0.25 0.025 0.107
rs2139612 X 92614916 A C 6.26E−03 0.68 0.412 0.542 7.28E−03 0.61 0.395 0.549
rs7860748 9 114202502 KIAA0368 G A 5.70E−03 0.63 0.381 0.492 9.79E−03 0.59 0.358 0.492
rs17029538 2 65096600 A C 2.02E−04 0.26 0.028 0.097 4.36E−01 0.65 0.027 0.041
kgp1371881 16 76291607 A G 6.85E−03 0.53 0.083 0.160 6.32E−03 0.46 0.075 0.164
rs10492882 16 76293394 A G 1.03E−02 0.55 0.083 0.155 3.04E−03 0.44 0.075 0.172
rs9393727 6 26500011 C G 2.78E−03 0.46 0.074 0.150 2.76E−03 0.44 0.108 0.213
0 - Priority rs1894408 6 32766833 C G 3.02E−03 1.72 0.419 0.305 9.30E−03 1.82 0.407 0.279
genes,
Predictive
Model
rs2839117 21 47550754 COL6A2 G A 1.24E−02 0.59 0.134 0.213 1.25E−03 0.45 0.137 0.262
kgp8437961 2 99960003 EIF58 G A 2.79E−03 0.50 0.099 0.183 1.07E−02 0.48 0.110 0.197
rs1508102 11 116379889 G A 4.99E−04 0.34 0.043 0.117 4.52E−02 0.50 0.060 0.115
rs4449139 2 124675366 CNTNAP5 G A 5.12E−03 0.63 0.189 0.504 3.76E−03 0.55 0.408 0.557
rs11559024 19 45821183 CKM A G 2.50E−03 Zero 0.000 0.029 1.18E−02 0.15 0.005 0.033
2 - Priority rs1894407 6 32767036 C A 1.75E−03 1.77 0.419 0.300 1.81E−02 1.72 0.403 0.287
genes
2 - Priority rs2857103 6 32791299 TAP2 C A 5.72E−03 1.70 0.369 0.269 4.13E−03 2.04 0.356 0.221
genes
2 - Priority rs9501224 6 32792910 TAP2 G A 6.53E−03 1.69 0.369 0.271 4.13E−03 2.04 0.356 0.221
genes
0 - Priority in kgp8110667 22 32716792 G A 5.97E−03 Infinity 0.030 0.000 1.46E−02 Infinity 0.050 0.000
Predictive
Model
0 - Priority kgp6599438 20 40843626 PTPRT G A 3.70E−03 0.21 0.010 0.046 1.55E−02 0.28 0.018 0.057
genes,
Predictive
Model
2 - Priority rs241451 6 32796480 TAP2 A G 6.26E−03 1.69 0.365 0.267 1.13E−02 1.86 0.354 0.233
genes
2 - Priority rs1894406 6 32787056 G A 2.63E−03 1.74 0.402 0.288 1.73E−02 1.76 0.361 0.246
genes
2 - Priority rs3218328 22 37524006 IL2RB G A 1.09E−02 0.16 0.005 0.030 1.39E−03 0.10 0.003 0.025
genes
2 - Priority rs241443 6 33797115 TAP2 A C 1.05E−02 1.63 0.367 0.273 5.28E−03 2.01 0.349 0.217
genes
2 - Priority rs2621323 6 32786707 A G 1.90E−02 1.56 0.371 0.286 3.09E−03 2.07 0.363 0.221
genes
2 - Priority kgp304921 20 14017077 MACROD2 A G 3.43E−02 0.50 0.038 0.081 1.51E−02 0.32 0.020 0.066
genes
2 - Priority rs241456 6 32795965 TAP2 G A 2.12E−02 1.55 0.313 0.229 8.54E−03 2.00 0.299 0.180
genes
0 - Priority kgp7747883 18 74804250 MBP G A 3.55E−02 0.70 0.346 0.429 9.82E−03 0.57 0.325 0.451
genes,
Predictive
Model
2 - Priority rs2621321 6 32789480 A G 2.38E−02 1.54 0.316 0.233 7.19E−03 2.05 0.300 0.180
genes
2 - Priority rs2857104 6 32790167 TAP2 G C 2.38E−02 1.54 0.316 0.233 7.89E−03 2.03 0.299 0.180
genet
2 - Priority rs241454 6 32796144 TAP2 A G 2.57E−02 1.51 0.315 0.233 7.80E−03 2.02 0.300 0.180
genes
2 - Priority rs241447 6 32796761 TAP2 A G 2.85E−02 1.52 0.313 0.233 8.34E−03 2.01 0.303 0.183
genes
2 - Priority kgp974569 6 32796057 TAP2 G A 2.85E−02 1.52 0.313 0.233 7.80E−03 2.02 0.300 0.180
gents
2 - Priority rs2857101 6 32794676 TAP2 A G 2.48E−02 1.53 0.312 0.231 9.33E−03 2.00 0.296 0.180
genes
2 - Priority kgp10224254 6 32785904 C A 5.85E−03 1.63 0.424 0.317 4.44E−02 1.58 0.386 0.287
genes
2 - Priority rs241444 6 32797109 TAP2 G A 2.85E−02 1.52 0.313 0.233 8.54E−03 2.00 0.299 0.180
genes
2 - Priority kgp4479467 6 32629331 HLA-DQB1 A G 2.83E−01 1.50 0.391 0.300 1.59E−02 1.80 0.374 0.262
genes
2 - Priority kgp10632945 20 4682507 G A 1.87E−02 0.62 0.177 0.254 3.48E−02 0.59 0.170 0.254
genes
2 - Priority rs241446 6 32796967 TAP2 G A 2.49E−02 1.53 0.311 0.229 1.09E−02 1.96 0.295 0.180
genes
2 Priority rs241453 6 32796226 TAP2 G A 3.06E−02 1.50 0.311 0.233 7.80E−03 2.02 0.300 0.180
genes
2 - Priority rs241449 6 32796653 TAP2 C A 3.25E−02 1.50 0.308 0.229 9.22E−03 1.99 0.298 0.180
genes
0 - Priority rs10162089 13 31316738 ALOX5AP G A 7.79E−03 1.56 0.508 0.398 3.16E−02 1.58 0.457 0.344
genes,
Predictive
Model
2 - Priority rs2071469 6 32784783 HLA-DOB G A 6.76E−03 1.62 0.426 0.321 4.44E−02 1.58 0.386 0.287
genes
2 - Priority P1_M_061510_6_159_P 6 32795505 TAP2 I D 3.66E−02 1.49 0.310 0.233 7.80E−03 2.02 0.300 0.180
genes
2 - Priority rs241452 6 32796346 TAP2 A G 3.31E−02 1.50 0.313 0.235 8.43E−01 2.01 0.299 0.180
genes
2 - Priority kgp2388352 6 32797297 TAP2 A G 4.25E−02 1.47 0.311 0.235 7.06E−03 2.02 0.304 0.180
genes
2 - Priority kgp8033704 6 32796521 TAP2 G A 3.51E−02 1.50 0.310 0.233 8.61E−03 2.02 0.296 0.180
genes
2 - Priority rs241442 6 32797168 TAP2 G A 3.94E−02 1.48 0.311 0.235 7.80E−03 2.02 0.300 0.180
genes
2 - Priority rs241445 6 32797072 TAP2 G A 3.57E−02 1.49 0.312 0.235 8.54E−03 2.00 0.299 0.180
genes
2 - Priority rs1410779 9 5083173 JAK2 G A 1.93E−02 0.61 0.145 0.217 1.29E−02 0.54 0.178 0.279
genes
2 - Priority kgp23672937 7 18685891 HDAC9 G A 4.94E−02 0.15 0.003 0.017 9.97E−03 Zero 0.000 0.016
genes
2 - Priority kgp4346717 18 74810199 MBP G A 4.94E−02 0.15 0.003 0.017 9.97E−03 Zero 0.000 0.016
genes
2 - Priority kgp9699754 10 79358319 KCNMA1 A G 2.70E−02 Infinity 0.020 0.000 4.11E−02 Infinity 0.033 0.000
genes
2 - Priority rs241440 6 32797361 TAP2 G A 3.40E−02 1.50 0.311 0.233 1.09E−02 1.96 0.295 0.180
genes
2 - Priority kgp5334779 6 3262842 HLA-DQB1 G A 1.68E−02 1.53 0.391 0.298 2.74E−02 1.73 0.362 0.262
genes
2 - Priority kgp4898719 6 32629347 HLA-DQB1 A G 2.53E−02 1.48 0.391 0.304 1.87E−02 1.77 0.372 0.262
genes
0 - Priority in rs759458 2 65243365 SLC1A4 G A 1.08E−03 1.90 0.303 0.183 4.74E−01 1.18 0.288 0.254
Predictive
Model
2 - Priority rs2071472 6 32784620 HLA-DOB G A 2.91E−02 1.49 0.348 0.267 1.86E−02 1.79 0.331 0.221
genes
2 - Priority rs2071470 6 32784753 HLA-DOB A G 2.91E−02 1.49 0.348 0.267 1.86E−02 1.79 0.331 0.221
genes
2 - Priority kgp25543811 18 74774894 MBP, MBP G A 4.81E−02 0.15 0.003 0.017 1.37E−02 0.10 0.002 0.025
genes
2 - Priority kgp293787 20 40905098 PTPRT G A 4.86E−03 0.15 0.005 0.038 2.19E−02 0.39 0.032 0.082
genet
2 - Priority rs2043136 3 30720304 TGFBR2 A G 4.42E−02 1.47 0.306 0.233 3.75E−02 1.67 0.308 0.208
genes
2 - Priority rs4769060 13 31337877 ALOX5AP A G 3.14E−02 1.42 0.472 0.383 3.13E−02 1.60 0.438 0.328
genes
2 - Priority kgp6032617 13 31287981 ALOX5AP A G 3.11E−02 0.68 0.212 0.292 4.38E−02 0.62 0.233 0.320
genes
2 - Priority kgp5441587 6 32827356 PSMB9 G A 4.56E−02 0.14 0.003 0.017 1.97E−02 0.23 0.010 0.041
genes
2 - Priority rs241435 6 32798243 TAP2, TAP2 G A 4.94E−02 0.15 0.003 0.017 1.97E−02 0.23 0.010 0.041
genes
2 - Priority kgp3182607 6 32823948 PSMB9 G A 4.94E−02 0.15 0.003 0.017 1.97E−02 0.23 0.010 0.041
genes
2 - Priority kgp22778566 7 1950337 MADIL1 G A 3.10E−02 1.56 0.276 0.199 2.87E−02 1.95 0.216 0.131
genes
2 - Priority kgp97310 9 3122932 JAK2 A G 4.58E−02 0.68 0.174 0.242 1.99E−02 0.58 0.225 0.328
genes
2 - Priority kgp5440506 13 31320543 ALOX5AP G A 3.52E−02 0.71 0.393 0.479 2.50E−02 0.63 0.462 0.583
genes
2 - Priority rs11147439 13 31323643 ALOX5AP C A 4.34E−02 0.72 0.396 0.479 2.16E−02 0.62 0.460 0.582
genes
2 - Priority rs4360791 13 31318020 ALOX5AP G A 4.65E−02 0.72 0.409 0.492 2.32E−02 0.63 0.470 0.590
genes
2 - Priority rs9671182 13 31321138 ALOX5AP C G 3.90E−02 0.71 0.398 0.483 2.76E−02 0.64 0.465 0.582
genes
2 - Priority rs4356334 13 31319546 ALOX5AP A G 3.98E−02 0.71 0.399 0.483 2.76E−02 0.64 0.465 0.582
genes
2 - Priority rs10815160 9 5116616 JAK2 A C 3.58E−02 0.66 0.180 0.252 3.69E−02 0.62 0.234 0.328
genes
2 - Priority rs4254166 13 31322949 ALOX5AP A G 4.97E−02 0.72 0.399 0.479 2.40E−02 0.63 0.463 0.582
gents
2 - Priority kgp2715873 13 31320249 ALOX5AP G A 4.97E−02 0.72 0.399 0.479 2.76E−02 0.64 0.465 0.582
genes
2 - Priority rs9670531 13 31321069 ALOX5AP A G 4.97E−02 0.72 0.399 0.479 2.76E−02 0.64 0.465 0.582
genes
1 - Priority rs2487896 10 100302380 HPSE2 G A 5.73E−01 0.88 0.139 0.155 5.50E−04 0.39 0.122 0.246
variants
0 - Priority rs3135391 6 32410987 HLA-DRA G A 3.99E−02 0.66 0.174 0.242 4.99E−02 0.64 0.231 0.320
variants,
Predictive
Model
2 - Priority kgp26271158 6 32823393 PSMB9 G A 4.94E−02 0.15 0.003 0.017 4.15E−02 0.29 0.012 0.041
genes
1 Priority rs3135388 6 32413051 G A 4.72E−02 0.67 0.174 0.239 4.99E−02 0.64 0.231 0.320
variants
2 - Priority kgp11281589 7 1941003 MADIL1 A G 4.53E−02 1.49 0.282 0.211 4.24E−02 1.85 0.210 0.131
genes
1 - Priority rs17575455 2 76424220 C A 4.13E−01 0.87 0.331 0.363 6.21E−03 0.56 0.308 0.443
variants
1 - Priority rs947603 10 95249605 A G 5.39E−02 1.48 0.258 0.192 1.59E−01 1.45 0.225 0.164
variants
Combined
Minor Allele
Allele Freq. DD Dd dd
STANDARD PHENOTYPE Odds Freq. (Non- DD (Non- Dd (Non- dd (Non-
Major Minor P-value Ratio (Re- (Re- (Re- re- (Re- re- (Re- re-
Prioritized Chromo- Posi- Allele Allele (Armitage (Minor spond- spond- spond- spond- spond- spond- spond- spond-
Variants Name some tion Gene(s) (d) (D) Test) Allele) ers) ers) ers) ers) ers) ers) ers) ers)
0 - Priority in kgp24415534 2 174156875 G A 3.98E−07 0.08 0.004 0.044 0 0 3 16 396 165
Predictive
Model
kgp12008955 2 73759636 ALMS1 G A 3.98E−07 0.09 0.004 0.044 0 0 3 16 396 165
kgp26026546 13 79972606 RBM26 A C 4.46E−07 0.03 0.001 0.036 0 0 1 13 397 167
0 - Priority in rs16886004 7 78021500 MAGI2 A G 9.81E−07 2.79 0.199 0.089 6 2 147 28 246 149
Predictive
Model
kgp25952891 13 80027089 A G 1.41E−06 0.04 0.001 0.031 0 0 1 12 198 164
kgp3450875 16 57268931 RSPRY1 G A 1.99E−05 0.12 0.006 0.047 0 0 5 17 394 164
rs10251797 7 78025427 MAGI2 C A 2.21E−06 2.67 0.197 0.091 6 2 145 29 248 130
kgp2299673 20 16933074 G A 2.28E−06 0.19 0.014 0.064 0 0 11 23 388 158
kgp10594414 1 216039833 USH2A A G 2.44E−06 0.14 0.008 0.050 0 0 6 11 391 163
kgp1688752 21 43016736 G A 2.53E−06 0.33 0.040 0.113 1 2 30 37 368 142
kgp12230354 5 27037978 CDH9 A C 2.74E−06 0.19 0.013 0.061 0 0 10 22 386 159
rs543122 3 124165156 KALRN G A 3.17E−06 0.54 0.423 0.569 70 54 195 97 131 29
kgp6236949 2 60301030 A G 3.26E−06 0.54 0.283 0.423 30 34 166 15 203 62
kgp9627338 17 90155 RPH3AL A G 3.52E−06 0.45 0.105 0.207 6 7 71 61 320 113
kgp11141512 20 35283733 NDRG3 G A 4.12E−06 0.21 0.014 0.064 0 1 11 21 388 158
rs9579566 13 30980265 G A 4.19E−06 0.26 0.023 0.080 0 1 18 27 381 153
rs2816838 10 52714759 G A 4.79E−06 0.46 0.125 0.229 4 8 92 67 303 106
kgp4705854 12 19907696 G A 4.80E−06 0.55 0.315 0.456 41 38 169 89 189 54
rs9817308 3 124182136 KALRN A C 5.18E−06 0.55 0.429 0.572 71 55 199 96 127 29
0 - Priority in kgp8817856 6 32744440 G A 5.33E−06 0.53 0.392 0.528 50 44 208 103 135 34
Predictive
Model
0 - Priority in kgp6214351 11 75546691 UVRAG A G 5.51E−06 0.35 0.046 0.119 0 2 37 39 361 140
Predictive
Model
kgp2356388 16 119771577 IQCK G A 5.78E−06 0.46 0.133 0.235 4 5 98 75 297 101
kgp7416024 9 21453902 G A 6.06E−06 0.13 0.006 0.044 0 0 5 16 393 165
rs6718758 2 60528802 C A 6.08E−06 0.55 0.307 0.445 35 38 175 85 189 58
rs7579987 2 60307009 G C 6.43E−06 0.55 0.331 0.469 40 41 184 87 175 52
rs7217872 17 88988 RPH3AL G A 7.50E−06 0.47 0.108 0.207 6 7 74 61 319 113
rs13394010 2 60302746 A G 7.81E−06 0.56 0.330 0.467 39 41 185 86 175 53
rs7191155 16 19800213 IQCK A G 7.89E−06 0.46 0.113 0.233 4 5 97 74 295 101
rs9931167 16 19792598 IQCK G A 8.07E−06 0.46 0.133 0.233 4 5 98 74 297 101
rs11691553 2 60303554 C A 8.19E−06 0.56 0.330 0.467 39 41 183 86 174 53
rs11648129 16 19820694 IQCK A G 8.23E−06 0.47 0.132 0.232 4 5 97 74 297 102
kgp25216186 1 23758427 ASAP3 A G 8.36E−06 0.07 0.003 0.033 0 0 2 12 397 169
kgp29794723 10 18397332 A G 8.64E−06 0.25 0.020 0.072 0 0 16 26 383 155
rs3829539 16 19722366 C16orf88 A G 8.80E−06 0.47 0.133 0.233 4 5 98 74 296 101
rs6895094 5 141037277 ARAP3 A C 9.24E−06 0.57 0.368 0.508 56 46 181 92 161 43
kgp1009249 12 19838534 G A 9.55E−06 0.51 0.195 0.311 10 16 136 80 253 84
rs10203396 2 60305110 A G 9.72E−06 0.56 0.332 0.467 39 41 186 17 173 53
kgp3854160 16 19721806 C16orf88 G A 1.00E−05 0.47 0.133 0.232 4 5 98 74 297 102
rs6497396 16 19735697 IQCK A G 1.02E−05 0.48 0.143 0.246 6 6 102 77 290 98
rs13419758 2 60302920 G A 1.09E−05 0.56 0.332 0.467 40 41 185 87 174 53
rs8055485 16 19750051 IQCK A G 1.09E−05 0.47 0.133 0.232 4 5 98 74 296 102
rs9931211 16 19813605 IQCK A G 1.09E−05 0.47 0.133 0.232 4 5 98 74 296 102
kgp5869992 12 49219569 CACNB3 A G 1.13E−05 0.58 0.384 0.528 60 58 184 74 152 48
kgp9320791 2 60309952 C G 1.15E−05 0.56 0.333 0.467 39 41 187 87 172 53
kgp7730397 16 19740243 IQCK A G 1.17E−05 0.47 0.134 0.233 4 5 99 74 295 101
kgp11002881 11 118219897 CD3G A G 1.17E−05 0.10 0.004 0.036 0 0 3 13 394 167
kgp3205849 10 121531725 INPP5F A G 1.18E−05 0.53 0.178 0.295 13 18 115 69 269 91
kgp6127371 4 153856357 A G 1.23E−05 0.23 0.016 0.064 0 0 13 23 384 157
kgp10305127 11 99881768 CNTN5 A G 1.23E−05 0.44 0.084 0.173 3 6 61 50 334 123
rs6535882 4 153848128 G A 1.24E−05 0.23 0.016 0.064 0 0 13 23 386 158
kgp6700691 4 153849531 A G 1.24E−05 0.23 0.016 0.064 0 0 13 23 386 158
rs11029892 11 27269546 G A 1.23E−05 1.94 0.351 0.227 44 5 192 72 163 104
kgp270001 16 19750275 IQCK G A 1.27E−05 0.48 0.143 0.244 6 6 102 76 291 98
kgp8192546 12 19903173 G A 1.29E−05 0.55 0.236 0.359 21 23 146 84 232 74
kgp5068397 16 19756348 IQCK A G 1.32E−05 0.51 0.183 0.294 10 12 126 82 262 86
kgp10910719 16 19803199 IQCK C A 1.39E−05 0.47 0.133 0.231 4 5 98 73 297 102
kgp2959751 6 58719342 G A 1.39E−05 0.22 0.015 0.061 0 0 12 22 387 159
rs950928 16 19824638 IQCK A G 1.43E−05 0.48 0.138 0.236 4 5 102 75 293 100
rs1858973 16 19743649 IQCK A G 1.44E−05 0.48 0.134 0.232 4 5 99 74 295 102
rs2660214 10 52732452 A G 1.45E−05 0.48 0.128 0.227 4 8 94 66 301 107
kgp2709692 18 3000808 LPIN2 C A 1.45E−05 0.22 0.015 0.061 0 0 12 22 386 159
kgp11210903 22 30898906 SEC14L4 G A 1.48E−05 0.12 0.005 0.039 0 0 4 14 395 167
kgp8030775 8 6328607 MCPHI A C 1.48E−05 0.20 0.011 0.055 0 1 9 18 388 162
rs10841337 12 19897179 A G 1.56E−05 0.55 0.241 0.365 22 24 147 84 227 73
kgp8178358 14 70923024 ADAM21 A G 1.57E−05 0.12 0.005 0.039 0 0 4 14 393 167
kgp11843177 11 27316568 A G 1.59E−05 1.95 0.330 0.208 39 4 185 67 175 109
kgp23737989 7 97217288 G A 1.60E−05 0.04 0.001 0.028 0 0 1 10 398 171
rs7187976 16 19708196 C16orf62 A G 1.65E−06 0.49 0.144 0.244 6 6 103 76 290 98
rs17577980 6 32359821 HCG23 G A 1.66E−05 2.36 0.196 0.093 13 5 130 23 255 150
kgp5908616 2 60329823 A C 1.67E−05 0.57 0.320 0.453 37 42 181 80 180 59
kgp26995430 3 53359406 DCP1A G A 1.69E−05 0.14 0.006 0.041 0 0 5 15 394 166
kgp6996560 13 110124242 G A 1.69E−05 0.14 0.006 0.041 0 0 5 15 394 166
rs4782279 16 19759007 IQCK A C 1.71E−05 0.50 0.147 0.249 7 7 103 76 288 98
rs8053136 16 19767129 IQCK A C 1.76E−05 0.52 0.195 0.307 12 14 131 83 255 84
kgp11328629 10 120711084 G A 1.78E−05 2.95 0.137 0.052 6 0 97 19 295 162
kgp8200264 10 12858372 CAMKID A G 1.87E−05 0.30 0.026 0.083 0 2 21 26 376 152
kgp6835138 20 40712994 PTPRT G A 1.88E−05 0.17 0.009 0.047 0 0 7 17 392 164
kgp841428 5 141036337 ARAP3 A G 1.93E−05 0.58 0.371 0.506 56 46 183 91 159 44
rs3815822 16 29872361 CDIPT A G 1.96E−05 1.74 0.509 0.373 102 26 202 83 95 72
rs1579771 3 157278882 C3orf55 A C 1.96E−05 1.91 0.366 0.246 39 9 213 71 146 101
kgp4734301 11 27315427 A G 1.96E−05 1.93 0.330 0.210 39 4 185 68 175 109
rs11029928 11 27319188 G A 1.96E−05 1.93 0.330 0.210 39 4 185 68 175 109
rs10941322 12 19866642 G A 2.00E−05 0.55 0.234 0.354 20 21 147 86 232 74
kgp1786079 7 144701118 A G 2.08E−05 0.49 0.118 0.215 4 11 86 56 306 114
kgp5053636 2 205356730 C A 2.13E−05 0.29 0.024 0.077 1 0 17 28 378 153
kgp9601342 9 18959317 FAM154A G A 2.21E−05 0.33 0.031 0.092 0 3 25 27 372 149
kgp8183049 13 40634155 G A 2.23E−05 Zero 0.000 0.022 0 0 0 8 399 172
kgp5564995 6 26414060 BTN3A1 C A 2.28E−05 2.88 0.145 0.061 1 0 109 21 274 151
kgp27500525 9 30278677 A G 2.35E−05 Zero 0.000 0.022 0 0 0 8 399 173
rs11022778 11 13390860 ARNTL A C 2.37E−05 1.86 0.351 0.227 52 5 176 72 171 104
kgp10826273 2 176163817 G A 2.41E−05 Zero 0.000 0.022 0 0 0 0 398 173
rs2494712 3 116796116 A G 2.44E−05 2.08 0.247 0.138 23 2 151 46 225 133
kgp1779154 12 73686930 A G 2.47E−05 0.08 0.003 0.031 0 0 2 11 397 169
kgp6190988 5 10699522 DAP G A 2.47E−05 0.08 0.003 0.031 0 0 2 11 397 169
kgp6507761 7 319681 A G 2.55E−05 0.59 0.428 0.566 78 61 185 83 135 37
rs2074037 16 19725130 C16orf88 G A 2.55E−05 0.49 0.137 0.232 4 5 101 73 294 101
rs4143493 6 51829939 PKHD1 G A 2.57E−05 4.21 0.090 0.025 0 0 72 9 327 172
kgp1699628 6 18032535 A G 2.72E−05 0.57 0.454 0.584 72 62 218 85 109 32
rs7024953 9 18960334 FAM154A A G 2.74E−05 0.34 0.031 0.091 0 3 23 27 372 131
kgp10974833 13 77319132 A G 2.78E−05 0.08 0.003 0.030 0 0 2 11 393 170
kgp10412303 2 205303530 G A 2.73E−05 0.30 0.026 0.080 0 1 21 27 376 133
kgp9669946 17 63733872 NOL11 A G 2.86E−05 0.53 0.167 0.272 12 10 109 78 276 92
rs17224858 3 124105297 KALRN G A 2.89E−05 0.54 0.188 0.298 10 19 130 70 239 92
rs6840089 4 153713220 ARFIP1 G A 3.06E−05 0.24 0.016 0.061 0 0 13 22 386 159
rs7666442 4 153753101 ARFIP1 A G 3.06E−05 0.24 0.016 0.061 0 0 13 22 386 159
rs7672014 4 153818501 ARFIP1 G A 3.06E−05 0.24 0.016 0.061 0 0 13 22 386 159
rs7677801 4 153795067 ARFIP1 A G 3.15E−05 0.24 0.016 0.061 0 0 13 22 383 158
rs4669694 2 11263948 FLJ33534 G A 3.15E−05 0.46 0.088 0.173 2 6 66 50 328 123
kgp10523170 16 5221617 G A 3.16E−05 0.08 0.003 0.033 0 1 2 10 397 170
kgp5216209 3 170740453 SLC2A2 C A 3.18E−05 0.23 0.015 0.058 0 0 12 21 387 159
rs720176 16 19721515 C16orf88 A G 3.20E−05 0.49 0.138 0.232 4 5 101 74 290 102
kgp7481870 16 19729016 C16orf88, G C 3.20E−05 0.49 0.146 0.242 4 5 107 77 282 98
IQCK
rs1532365 12 49204421 G A 3.23E−05 0.59 0.345 0.478 43 52 188 68 166 60
rs12943140 17 65718771 NOL11 G A 3.24E−05 0.53 0.167 0.272 12 10 108 78 273 92
kgp11702474 4 153712868 ARFIP1 A G 3.31E−05 0.24 0.016 0.061 0 0 13 22 384 159
rs10498793 6 31139707 PKHD1 G A 3.34E−05 4.14 0.089 0.025 0 0 71 9 328 172
kgp6539666 3 157292022 C3orf55 A G 3.39E−05 1.90 0.354 0.240 34 7 213 73 150 101
kgp10679353 16 19800133 IQCK G A 3.39E−05 0.50 0.144 0.240 5 7 105 73 289 101
kgp9410843 10 121484477 A G 3.48E−05 0.55 0.180 0.290 13 18 116 69 266 94
kgp6772915 9 18978739 FAM154A A C 3.50E−05 0.33 0.032 0.089 0 2 25 28 371 149
kgp20478926 8 21050249 A G 3.53E−05 0.44 0.030 0.106 5 13 14 8 377 156
kgp10619195 4 99417717 TSPAN5 A G 3.54E−05 0.36 0.040 0.102 0 2 32 33 366 146
rs1544352 16 19713183 A G 3.54E−05 0.50 0.142 0.238 6 5 101 76 290 100
kgp15390522 1 205017963 CNTN2 G A 3.59E−05 0.11 0.004 0.033 0 0 3 12 396 169
kgp24727706 22 49286357 LOC100128946 G A 3.60E−05 0.24 0.015 0.058 0 0 12 21 386 160
rs931570 12 49195124 G A 3.61E−05 0.59 0.344 0.475 43 51 187 70 167 60
kgp10591989 17 65697118 A G 3.63E−05 0.49 0.111 0.202 7 5 74 63 317 113
kgp12557319 6 8794609 A G 3.69E−05 0.11 0.004 0.013 0 0 3 12 395 169
kgp345301 16 19730354 IQCK A C 3.69E−05 0.49 0.134 0.228 4 5 98 71 293 102
kgp8615910 5 30927198 A T 3.72E−05 0.49 0.123 0.215 4 7 90 64 304 110
kgp2245775 13 91402506 G A 3.76E−05 0.55 0.221 0.311 13 18 150 84 235 79
kgp29367521 4 134471944 G A 3.81E−05 0.13 0.005 0.036 0 0 4 13 395 166
kgp7506434 1 13823114 LRRC38 A G 3.83E−05 0.11 0.004 0.036 0 1 3 11 395 169
rs4780822 16 19727993 C16orf88, A G 3.83E−05 0.50 0.143 0.238 5 6 103 74 288 101
IQCK
kgp512180 16 10829457 G A 3.89E−05 0.56 0.232 0.347 19 22 147 81 233 77
rs1604169 5 84213343 A C 3.91E−05 0.57 0.355 0.478 41 40 201 93 157 48
kgp25921291 13 78418857 G A 3.92E−05 0.17 0.008 0.044 0 1 6 14 393 163
rs16901784 6 26553433 C A 4.02E−05 0.47 0.089 0.174 2 8 67 47 329 126
kgp6228750 1 110261382 A G 4.06E−05 0.35 0.035 0.094 1 1 26 32 372 148
kgp9354820 15 93793636 G A 4.07E−05 0.14 0.005 0.039 0 1 4 12 395 168
kgp8106690 12 128734969 A G 4.09E−05 0.51 0.135 0.232 8 9 90 66 296 106
kgp5144181 2 30364733 G A 4.10E−05 0.32 0.029 0.083 1 0 21 30 377 151
kgp9627406 9 132997137 NCS1 G A 4.10E−05 0.38 0.048 0.120 0 4 35 30 328 124
kgp2262166 9 18960391 FAM154A A C 4.15E−05 0.35 0.033 0.091 0 3 26 27 373 131
kgp4223880 2 10584122 ODC1 A G 4.19E−05 0.13 0.005 0.036 0 0 4 13 394 167
kgp61811 1 160346794 A C 4.19E−05 0.14 0.005 0.039 0 1 4 12 394 168
kgp9421884 19 11049860 G A 4.23E−05 0.39 0.048 0.113 0 3 38 35 361 143
rs8050872 16 19803846 IQCK G A 4.27E−05 0.51 0.149 0.246 7 7 105 75 287 99
rs7864679 9 18945161 FAM154A G A 4.34E−05 0.35 0.033 0.091 0 3 26 27 372 151
kgp2446153 5 152980439 GR1A1 G A 4.35E−05 0.13 0.005 0.036 0 0 4 13 395 168
kgp7804623 1 41125455 RIMS3 G A 4.36E−05 1.82 0.341 0.221 47 8 178 64 174 109
rs3792135 2 100062163 REV1 A G 4.38E−05 0.51 0.125 0.219 4 10 91 59 300 111
rs8035826 15 94832144 C A 4.40E−05 1.71 0.489 0.358 97 22 195 85 106 73
kgp85534 2 14374582 G A 4.57E−05 0.20 0.010 0.047 0 0 8 17 391 163
rs11192461 10 107266483 G A 4.60E−05 0.45 0.084 0.163 1 4 65 51 333 126
kgp297178 9 18942615 FAM154A G A 4.66E−05 0.34 0.030 0.086 0 2 24 27 375 152
kgp2045074 6 51187450 C A 4.74E−05 0.13 0.005 0.036 0 0 4 13 392 168
rs10049206 3 157211691 G A 4.80E−05 1.85 0.362 0.249 38 9 213 72 148 100
rs9834010 3 137216222 C A 4.80E−05 1.85 0.362 0.249 38 9 213 72 148 100
kgp971582 6 51911703 PKHD1 A G 4.82E−05 3.60 0.098 0.030 2 0 74 11 323 170
kgp22791211 X 92601376 G A 4.82E−05 0.64 0.394 0.542 93 65 126 65 177 50
kgp4573213 3 124199924 KALRN A G 4.83E−05 0.35 0.191 0.298 10 19 132 70 256 92
kgp19568724 14 21486590 NDRG2 G A 4.84E−05 0.15 0.006 0.039 0 0 5 14 394 167
kgp9071686 9 21419161 G A 4.84E−05 0.15 0.006 0.039 0 0 5 14 394 167
kgp652534 4 13612731 BODIL C G 4.84E−03 0.15 0.006 0.039 0 0 5 14 394 167
kgp1224440 1 247199991 A C 4.87E−05 0.50 0.109 0.199 2 11 83 50 314 120
kgp2465184 9 18942204 FAM154A A C 4.87E−05 0.34 0.030 0.086 0 2 24 17 374 152
kgp11543962 10 109379303 G A 4.88E−05 0.17 0.008 0.042 0 0 6 15 392 165
kgp4543470 2 213359411 A C 4.90E−05 0.51 0.134 0.227 5 7 96 68 296 106
kgp5579170 17 65681762 PITPNC1 G A 4.94E−05 0.46 0.084 0.165 5 2 57 55 336 122
kgp4812831 6 51910905 PKHD1 A G 4.94E−05 3.62 0.095 0.030 1 0 75 11 323 170
rs2598360 9 114133899 KIAA0368 G A 5.01E−05 0.59 0.373 0.500 51 48 196 85 152 48
kgp10633631 8 17504188 MTUS1 A G 5.02E−05 Zero 0.000 0.025 0 1 0 7 399 173
kgp3651787 16 84992155 G A 5.08E−05 0.17 0.008 0.041 0 0 6 15 393 166
rs823829 9 114105079 A C 5.10E−05 0.59 0.398 0.525 57 52 204 86 138 43
kgp279772 8 2105376 T A 5.15E−05 0.57 0.247 0.362 25 20 146 91 226 70
kgp20163979 8 79366479 A C 5.17E−05 0.05 0.001 0.025 0 0 1 9 398 172
kgp21171930 4 80362934 A G 5.17E−05 0.05 0.001 0.025 0 0 1 9 398 172
kgp2092817 5 39632583 G A 3.17E−05 0.05 0.001 0.025 0 0 1 9 398 172
kgp3598409 13 31632449 GLDN G A 5.17E−05 0.05 0.001 0.025 0 0 1 9 398 172
kgp6469620 1 41233946 NFYC G A 5.21E−05 1.74 0.410 0.285 64 18 198 67 136 96
rs3818675 10 12838045 CAMKID G A 5.23E−05 0.32 0.025 0.077 0 2 20 24 378 155
kgp9530088 11 30501034 MPPED2 A G 5.23E−05 0.57 0.241 0.364 25 21 146 89 224 70
rs2453478 12 49302743 A G 5.25E−05 0.60 0.341 0.478 45 52 186 69 165 60
kgp10558725 18 3070717 MYOM1 G A 5.25E−05 0.18 0.009 0.044 0 0 7 16 391 165
kgp28586329 8 6304848 MCPH1 A G 5.30E−05 0.05 0.001 0.025 0 0 1 9 397 172
kgp30282494 5 72863824 UTP15 A G 5.30E−05 0.05 0.001 0.025 0 0 1 9 397 172
rs7524848 1 41106774 RIMS3 A C 5.35E−05 1.81 0.342 0.224 47 8 179 65 173 108
kgp9806386 5 138068034 A C 5.42E−05 0.05 0.001 0.025 0 0 1 9 396 173
kgp4137859 6 32434481 A G 5.43E−05 2.32 0.180 0.091 8 0 127 33 263 148
kgp1753445 21 39811162 ERG G A 5.45E−05 2.40 0.169 0.083 6 0 123 30 270 150
kgp9354462 2 149894403 A C 5.45E−05 0.59 0.297 0.420 37 32 162 88 198 61
kgp26533576 6 99139641 A C 5.57E−05 0.17 0.008 0.041 0 0 6 15 390 166
kgp2023214 16 76293345 A G 5.66E−05 0.49 0.080 0.166 8 8 48 44 342 129
kgp6768546 4 133864174 FHDC1 G A 5.85E−05 0.26 0.018 0.061 0 0 14 32 385 158
kgp1098237 9 114173681 KIAA0368 G A 5.98E−05 0.60 0.368 0.494 52 46 190 86 157 48
kgp4559907 6 133253232 G A 6.02E−05 0.60 0.331 0.456 46 37 171 91 180 53
rs1644418 10 12838409 CAMKID A G 6.11E−05 0.31 0.024 0.075 0 2 19 33 380 156
kgp11804835 6 32396146 C A 6.12E−05 2.35 0.170 0.083 8 1 119 28 270 132
rs7029123 9 114136169 KIAA0368 A G 6.19E−05 0.60 0.375 0.500 52 48 195 85 152 48
kgp2688306 7 28560259 CREB5 A G 6.20E−05 2.90 0.122 0.047 3 1 91 15 304 164
kgp2618591 8 108994382 RSPO2 G A 6.21E−05 0.36 0.041 0.099 0 0 33 36 366 145
rs2845371 22 17178213 G A 6.21E−05 1.70 0.487 0.361 93 21 198 88 103 71
kgp5409955 9 18980841 FAM154A G A 6.27E−05 0.34 0.029 0.083 0 2 23 26 374 153
rs7228827 18 76900411 ATP9B G A 6.28E−05 2.12 0.206 0.108 20 1 124 37 254 143
kgp1912531 2 137850215 TH5D7B A G 6.34E−05 2.12 0.204 0.105 18 4 126 30 254 147
kgp4162414 6 51868165 PKHD1 G A 6.35E−05 3.56 0.095 0.030 1 0 74 11 324 170
rs2926455 10 107260501 A G 6.37E−05 0.46 0.086 0.165 1 4 67 51 331 124
kgp1669685 7 78028723 MAGI2 A C 6.38E−05 1.98 0.254 0.150 21 4 159 46 216 130
kgp7059449 2 41255455 A C 6.39E−05 4.93 0.074 0.017 1 0 57 6 340 175
rs3899755 X 68447361 C A 6.44E−05 2.00 0.216 0.108 34 4 104 31 261 146
rs2309760 4 183591133 ODZ3 A G 6.56E−05 0.61 0.344 0.472 53 44 168 83 177 54
kgp2788291 18 45153979 G A 6.64E−05 0.51 0.120 0.211 5 9 86 58 308 113
kgp3933330 7 28563709 CREB5 A G 6.67E−05 2.26 0.178 0.086 15 1 111 29 271 151
rs7062312 X 68447052 G A 6.68E−05 2.01 0.215 0.108 33 4 105 31 260 146
kgp337461 6 125019969 NKAIN2 A G 6.76E−05 0.51 0.123 0.214 9 5 80 67 310 108
rs6899068 5 126591501 G A 6.78E−05 1.75 0.405 0.285 62 13 199 77 138 91
kgp8046214 4 153726582 ARFIP1 A G 6.80E−05 0.25 0.016 0.058 0 0 13 21 386 159
rs6835202 4 153855186 C A 6.80E−05 0.25 0.016 0.058 0 0 13 21 386 159
kgp10620244 8 133472755 KCNQ3 G A 6.83E−05 2.05 0.219 0.119 20 4 135 35 244 142
kgp11407560 2 65096583 A G 6.84E−05 0.31 0.025 0.075 1 0 18 27 380 153
rs3799383 6 26510748 G A 6.85E−05 0.48 0.089 0.171 2 8 67 46 329 127
rs6845927 4 153799603 ARFIP1 A C 6.87E−05 0.26 0.018 0.061 0 0 14 22 383 159
rs10489312 1 175526526 TNR A G 6.87E−05 0.52 0.128 0.221 6 10 90 60 302 111
kgp11633966 11 37701793 G A 6.88E−05 0.54 0.150 0.249 11 10 98 70 290 101
rs7496451 15 25718875 G A 6.89E−05 2.01 0.239 0.138 23 0 145 50 231 131
kgp1048169 4 78109591 G A 6.94E−05 0.51 0.108 0.196 5 9 76 53 318 119
kgp8990121 9 27215039 TEK C A 6.94E−05 2.35 0.167 0.080 10 0 113 29 276 152
kgp26528455 6 72737785 RIMS1 G A 6.99E−05 0.28 0.018 0.064 1 1 12 21 386 159
kgp4755147 2 149894654 A C 7.15E−05 0.59 0.301 0.422 38 32 161 88 195 60
kgp10372946 10 113980657 JAKMIP3 G A 7.17E−05 10.53 0.053 0.006 0 0 42 2 357 179
rs1380706 2 57864042 A G 7.29E−05 1.72 0.409 0.285 64 17 190 68 135 94
kgp12182745 8 125465203 TRMT12 A T 7.30E−05 0.43 0.047 0.117 3 6 31 30 357 144
kgp3951463 3 157280172 C3orf55 C A 7.32E−05 1.83 0.348 0.038 36 8 205 70 157 103
kgp8602316 7 335911 G A 7.36E−05 1.70 0.417 0.291 74 18 184 68 140 93
rs16927077 11 10620629 MRVII-AS1 G A 7.38E−05 0.47 0.010 0.157 2 5 60 47 337 129
kgp6959492 4 153687676 A G 7.39E−05 0.26 0.016 0.058 0 0 13 21 386 160
kgp8793915 11 109012665 A G 7.40E−05 Zero 0.000 0.019 0 0 0 7 399 173
kgp13161760 21 18192806 G A 7.40E−05 0.05 0.001 0.028 0 1 1 8 398 172
kgp6567154 4 3442146 G C 7.47E−05 0.59 0.274 0.392 28 32 161 78 207 71
kgp2282938 22 32719612 G A 7.47E−05 0.25 0.015 0.056 0 0 12 20 386 159
kgp355723 8 75370402 GDAPI A G 7.54E−05 0.09 0.003 0.028 0 0 2 10 396 169
rs10201643 2 149906641 LYPD6B C A 7.56E−05 0.60 0.301 0.422 40 32 160 88 199 60
kgp27640141 12 118805689 TAOK3 G A 7.57E−05 0.05 0.001 0.028 0 1 1 8 397 172
rs7670525 4 153814538 ARFIP1 A G 7.66E−05 0.26 0.016 0.058 0 0 13 21 385 160
kgp28817122 8 122487115 A G 7.66E−05 0.26 0.016 0.058 0 0 13 21 385 160
kgp5014707 9 1702186 G A 7.75E−05 Zero 0.000 0.019 0 0 0 7 399 174
kgp7092772 14 22379841 G A 7.75E−05 Zero 0.000 0.019 0 0 0 7 399 174
kgp3477351 19 295864 G A 7.75E−05 Zero 0.000 0.019 0 0 0 7 399 174
kgp23298674 21 20962564 C A 7.75E−05 Zero 0.000 0.019 0 0 0 7 399 174
kgp12083934 16 10128979 A G 7.75E−05 0.58 0.232 0.344 20 22 143 79 232 78
kgp485316 7 15372018 AGMO G A 7.80E−05 1.67 0.466 0.340 94 17 183 89 121 75
kgp25191871 1 115687027 A C 7.84E−05 0.33 0.026 0.078 0 2 21 24 376 153
kgp24131116 2 213906695 IKZF2 G A 7.91E−05 Zero 0.000 0.019 0 0 0 7 398 174
kgp9854133 3 31334098 G A 7.91E−05 Zero 0.000 0.019 0 0 0 7 398 174
kgp228119I8 X 21960214 SMS C A 8.00E−05 0.41 0.055 0.133 5 12 34 24 360 145
kgp7792268 13 23070499 C A 8.06E−05 0.24 0.013 0.052 0 1 10 17 388 163
kgp11316379 11 9814612 LOC283104, G A 8.09E−05 0.59 0.344 0.466 41 37 186 89 162 49
SBF2
kgp27571222 12 56243724 A G 8.10E−05 0.05 0.001 0.028 0 1 1 8 394 172
rs1986214 13 42948531 A G 8.21E−05 1.89 0.278 0.171 31 3 159 56 207 122
kgp1054273 12 67131774 G A 8.21E−05 0.09 0.003 0.028 0 0 2 10 397 171
kgp9551947 18 42502140 SETBP1 G A 8.21E−05 0.09 0.003 0.028 0 0 2 10 397 171
kgp5483926 3 144352913 A C 8.21E−05 0.09 0.003 0.028 0 0 2 10 397 171
kgp4155998 1 184734012 G A 8.21E−05 0.09 0.003 0.028 0 0 2 10 397 171
kgp2958113 5 163341388 A C 8.21E−05 0.09 0.003 0.028 0 0 2 10 397 171
kgp8335513 11 4926211 G A 8.21E−05 0.09 0.003 0.028 0 0 2 10 397 171
kgp5388938 8 79087167 G A 8.21E−05 0.09 0.003 0.028 0 0 2 10 397 171
kgp28687699 8 73225285 C A 8.21E−05 0.09 0.003 0.028 0 0 2 10 397 171
kgp11627530 14 78954642 NRXN3 A G 8.35E−05 0.43 0.059 0.128 0 3 47 36 352 139
kgp24753470 1 26013940 MANIC1 A C 8.41E−05 0.09 0.003 0.028 0 0 2 10 396 171
kgp1285441 3 56931141 ARHGEF3 G A 8.44E−05 0.52 0.130 0.221 8 6 88 68 303 107
rs17638791 6 51940816 PKHD1 A G 8.49E−05 3.35 0.098 0.033 1 0 76 12 322 169
rs2325911 6 125027223 NKAIN2 C A 8.57E−05 0.51 0.119 0.207 9 3 77 69 312 109
kgp10967046 15 66174387 MEGF11 G A 8.61E−05 0.36 0.035 0.091 1 1 26 31 371 149
rs12013377 X 92620062 A G 8.64E−05 0.65 0.405 0.547 97 66 129 66 173 49
kgp7186699 4 184878777 STOX2 G A 8.64E−05 3.55 0.094 0.028 4 1 67 8 328 172
kgp9368119 7 11707419 THSD7A A G 8.76E−05 0.60 0.385 0.506 52 47 203 89 144 45
kgp124162 11 72356846 PDE2A A G 8.78E−05 0.25 0.015 0.055 0 0 12 20 386 161
kgp8440035 4 78058785 G A 8.79E−05 0.30 0.019 0.066 1 2 13 20 385 159
rs4738738 8 59844254 TOX A C 8.80E−05 1.69 0.424 0.300 80 13 177 82 140 85
kgp7802182 19 56759170 A G 8.86E−05 0.57 0.208 0.315 19 16 128 82 252 83
kgp2923815 19 43931355 G A 8.87E−05 0.43 0.064 0.131 1 2 49 44 348 135
rs3767955 1 41104475 RIMS3 G A 8.91E−05 1.78 0.341 0.227 46 8 180 66 173 107
kgp3418770 10 59425598 A G 8.92E−05 10.31 0.052 0.006 0 0 41 2 354 178
rs17449018 9 7060825 KDM4C G A 8.97E−05 1.82 0.318 0.207 41 4 172 66 186 109
kgp4524468 22 32724312 A G 8.98E−05 1.89 0.281 0.172 27 8 165 45 198 124
kgp4418535 6 32431558 C A 9.00E−05 2.26 0.177 0.091 1 0 125 33 266 148
kgp22823022 X 9742468 G A 9.00E−05 0.36 0.133 0.236 17 16 70 51 305 109
kgp7063887 1 189928568 G A 9.14E−05 0.41 0.044 0.108 0 6 35 27 363 148
rs1621509 7 2969680 CARD11 G A 9.29E−05 2.00 0.239 0.142 15 4 160 43 222 133
kgp4842590 1 110249364 A C 9.32E−05 0.27 0.015 0.058 1 1 10 19 387 160
rs11192469 10 107282331 A G 9.38E−05 0.47 0.081 0.158 1 4 64 49 333 127
kgp8303520 7 154911234 C A 9.41E−05 0.61 0.412 0.539 68 56 188 82 137 42
rs1345334 2 60324127 A G 9.46E−05 0.60 0.357 0.478 47 42 191 88 161 50
rs9876830 3 157311299 C3orf55 G A 9.48E−05 1.82 0.348 0.240 35 8 208 71 156 102
kgp11285862 21 18177980 A G 9.56E−05 0.09 0.003 0.030 0 1 2 9 396 171
rs2824070 21 18205972 A G 9.57E−05 0.22 0.010 0.047 0 1 8 15 389 164
kgp7181058 14 98363696 G A 9.62E−05 0.24 0.014 0.052 0 0 11 19 388 162
kgp5002011 1 110265738 G A 9.66E−05 0.35 0.030 0.083 1 1 22 28 376 152
rs2139612 X 92614916 A C 9.68E−05 0.65 0.403 0.544 96 65 129 67 173 49
rs7860748 9 114202502 KIAA0368 G A 9.73E−05 0.61 0.370 0.492 52 46 191 86 156 49
rs17029538 2 65096600 A C 9.73E−05 0.33 0.028 0.078 1 0 20 28 378 152
kgp1371881 16 76291607 A G 9.74E−05 0.50 0.079 0.161 8 8 47 42 344 130
rs10492882 16 76293394 A G 9.74E−05 0.50 0.079 0.161 8 8 47 43 344 130
rs9393727 6 26500011 C G 9.75E−05 0.49 0.091 0.171 2 8 68 46 337 127
0 - Priority rs1894408 6 32766833 C G 9.82E−05 1.73 0.413 0.296 58 16 211 74 127 89
genes,
Predictive
Model
rs2839117 21 47550754 COL6A2 G A 9.85E−05 0.54 0.135 0.229 9 11 90 61 300 109
kgp8437961 2 99960003 EIF58 G A 9.85E−05 0.50 0.105 0.188 4 6 75 56 318 119
rs1508102 11 116379889 G A 9.87E−05 0.42 0.052 0.116 0 4 41 34 357 143
rs4449139 2 124675366 CNTNAP5 G A 9.93E−05 0.61 0.398 0.522 61 53 195 83 142 45
rs11559024 19 45821183 CKM A G 1.00E−04 0.09 0.003 0.030 0 1 3 9 394 171
2 - Priority rs1894407 6 32767036 C A 1.06E−04 1.73 0.411 0.296 57 16 213 75 128 90
genes
2 - Priority rs2857103 6 32791299 TAP2 C A 1.13E−04 1.78 0.362 0.253 39 11 211 69 149 100
genes
2 - Priority rs9501224 6 32792910 TAP2 G A 1.32E−04 1.77 0.362 0.254 39 11 211 70 149 100
genes
0 - Priority in kgp8110667 22 32716792 G A 1.44E−04 Infinity 0.040 0.000 1 0 30 0 367 181
Predictive
Model
0 - Priority kgp6599438 20 40843626 PTPRT G A 2.48E−04 0.26 0.014 0.050 0 0 11 18 386 163
genes,
Predictive
Model
2 - Priority rs241451 6 32796480 TAP2 A G 2.58E−04 1.72 0.360 0.256 39 12 207 68 150 100
genes
2 - Priority rs1894406 6 32787056 G A 2.66E−04 1.68 0.381 0.273 51 13 202 73 146 95
genes
2 - Priority rs3218328 22 37524006 IL2RB G A 2.96E−04 0.13 0.004 0.028 0 0 3 10 395 169
genes
2 - Priority rs241443 6 33797115 TAP2 A C 3.02E−04 1.71 0.358 0.254 40 11 202 69 152 99
genes
2 - Priority rs2621323 6 32786707 A G 3.33E−04 1.69 0.367 0.264 43 12 207 71 149 97
genes
2 - Priority kgp304921 20 14017077 MACROD2 A G 8.00E−04 0.41 0.029 0.075 2 2 19 23 373 154
genes
2 - Priority rs241456 6 32795965 TAP2 G A 8.63E−04 1.66 0.306 0.213 32 9 180 59 117 113
genes
0 - Priority kgp7747883 1 74804250 MBP G A 8.64E−04 0.64 0.335 0.436 43 33 181 92 174 56
genes,
Predictive
Model
2 - Priority rs2621321 6 32789480 A G 9.00E−04 1.66 0.308 0.215 31 9 183 60 184 112
genes
2 - Priority rs2857104 6 32790167 TAP2 G C 9.87E−04 1.65 0.307 0.215 31 9 183 60 185 112
genet
2 - Priority rs241454 6 32796144 TAP2 A G 1.02E−03 1.65 0.307 0.215 32 9 180 60 185 112
genes
2 - Priority rs241447 6 32796761 TAP2 A G 1.11E−03 1.64 0.308 0.217 32 9 180 60 184 111
genes
2 - Priority kgp974569 6 32796057 TAP2 G A 1.12E−03 1.64 0.307 0.215 32 9 180 60 186 112
gents
2 - Priority rs2857101 6 32794676 TAP2 A G 1.15E−03 1.64 0.305 0.214 31 9 181 59 187 112
genes
2 - Priority kgp10224254 6 32785904 C A 1.15E−03 1.56 0.405 0.307 59 18 205 75 135 88
genes
2 - Priority rs241444 6 32797109 TAP2 G A 1.22E−03 1.63 0.306 0.215 32 9 180 60 187 112
genes
2 - Priority kgp4479467 6 32629331 HLA-DQB1 A G 1.25E−03 1.58 0.383 0.287 54 11 195 82 147 88
genes
2 - Priority kgp10632945 20 4682507 G A 1.25E−03 0.61 0.173 0.254 10 11 312 70 270 100
genes
2 - Priority rs241446 6 32796967 TAP2 G A 1.26E−03 1.63 0.303 0.213 32 9 176 59 188 112
genes
2 Priority rs241453 6 32796226 TAP2 G A 1.31E−03 1.63 0.305 0.215 32 9 179 60 187 112
genes
2 - Priority rs241449 6 32796653 TAP2 C A 1.35E−03 1.63 0.303 0.212 32 9 175 58 188 112
genes
0 - Priority rs10162089 13 31316738 ALOX5AP G A 1.40E−03 1.51 0.482 0.380 96 24 190 88 110 67
genes,
Predictive
Model
2 - Priority rs2071469 6 32784783 HLA-DOB G A 1.40E−03 1.55 0.406 0.309 59 18 205 76 134 87
genes
2 - Priority P1 M 061510 6 159 P 6 32795505 TAP2 I D 1.41E−03 1.62 0.305 0.215 32 9 178 60 187 112
genes
2 - Priority rs241452 6 32796346 TAP2 A G 1.42E−03 1.62 0.306 0.217 32 9 179 60 186 111
genes
2 - Priority kgp2388352 6 32797297 TAP2 A G 1.46E−03 1.62 0.307 0.216 34 10 179 57 185 111
genes
2 - Priority kgp8033704 6 32796521 TAP2 G A 1.55E−03 1.63 0.303 0.215 29 9 183 60 186 112
genes
2 - Priority rs241442 6 32797168 TAP2 G A 1.56E−03 1.62 0.305 0.217 32 9 179 60 187 111
genes
2 - Priority rs241445 6 32797072 TAP2 G A 1.56E−03 1.62 0.305 0.217 32 9 179 60 187 111
genes
2 - Priority rs1410779 9 5083173 JAK2 G A 1.73E−03 0.61 0.161 0.238 8 10 112 66 277 105
genes
2 - Priority kgp23672937 7 18685891 HDAC9 G A 1.74E−03 0.07 0.001 0.017 0 0 1 6 398 175
genes
2 - Priority kgp4346717 1 74810199 MBP G A 1.74E−03 0.07 0.001 0.017 0 0 1 6 398 175
genes
2 - Priority kgp9699754 10 79358319 KCNMA1 A G 1.74E−03 Infinity 0.026 0.000 0 0 21 0 377 179
genes
2 - Priority rs241440 6 32797361 TAP2 G A 1.79E−03 1.61 0.303 0.215 32 9 177 60 189 112
genes
2 - Priority kgp5334779 6 3262842 HLA-DQB1 G A 1.87E−03 1.56 0.377 0.286 50 10 199 83 148 87
genes
2 - Priority kgp4898719 6 32629347 HLA-DQB1 A G 1.91E−03 1.55 0.382 0.290 54 11 195 83 148 87
genes
0 - Priority in rs759458 2 65243365 SLC1A4 G A 2.01E−03 1.59 0.295 0.207 38 7 159 61 201 113
Predictive
Model
2 - Priority rs2071472 6 32784620 HLA-DOB G A 2.21E−03 1.56 0.340 0.251 40 12 191 67 168 102
genes
2 - Priority rs2071470 6 32784753 HLA-DOB A G 2.21E−03 1.56 0.340 0.251 40 12 191 67 168 102
genes
2 - Priority kgp25543811 18 74774894 MBP, MBP G A 2.29E−03 0.12 0.003 0.019 0 0 2 7 397 173
genes
2 - Priority kgp293787 20 40905098 PTPRT G A 2.55E−03 0.37 0.019 0.052 0 2 15 15 384 164
genet
2 - Priority rs2043136 3 30720304 TGFBR2 A G 4.11E−03 1.53 0.307 0.225 38 7 167 67 191 106
genes
2 - Priority rs4769060 13 31337877 ALOX5AP A G 4.43E−03 1.45 0.455 0.365 87 22 189 88 123 71
genes
2 - Priority kgp6032617 13 31287981 ALOX5AP A G 4.44E−03 0.67 0.222 0.301 23 15 131 79 244 87
genes
2 - Priority kgp5441587 6 32827356 PSMB9 G A 6.10E−03 0.24 0.006 0.025 0 0 5 9 394 169
genes
2 - Priority rs241435 6 32798243 TAP2, TAP2 G A 6.85E−03 0.24 0.006 0.025 0 0 5 9 394 172
genes
2 - Priority kgp3182607 6 32823948 PSMB9 G A 6.85E−03 0.24 0.006 0.025 0 0 5 9 394 172
genes
2 - Priority kgp22778566 7 1950337 MADIL1 G A 7.00E−03 1.57 0.246 0.175 19 4 156 51 220 117
genes
2 - Priority kgp97310 9 3122932 JAK2 A G 7.79E−03 0.68 0.200 0.271 17 14 121 70 216 97
genes
2 - Priority kgp5440506 13 31320543 ALOX5AP G A 7.94E−03 0.72 0.428 0.514 81 45 175 95 138 40
genes
2 - Priority rs11147439 13 31323643 ALOX5AP C A 8.10E−03 0.72 0.429 0.514 81 45 180 96 138 40
genes
2 - Priority rs4360791 13 31318020 ALOX5AP G A 8.60E−03 0.72 0.440 0.525 85 48 181 94 133 39
genes
2 - Priority rs9671182 13 31321138 ALOX5AP C G 8.78E−03 0.72 0.432 0.517 82 45 180 96 136 39
genes
2 - Priority rs4356334 13 31319546 ALOX5AP A G 8.95E−03 0.72 0.432 0.517 82 46 181 95 136 40
genes
2 - Priority rs10815160 9 5116616 JAK2 A C 9.34E−03 0.68 0.207 0.278 19 14 124 71 248 93
genes
2 - Priority rs4254166 13 31322949 ALOX5AP A G 9.96E−03 0.72 0.431 0.514 81 45 182 96 136 40
gents
2 - Priority kgp2715873 13 31320249 ALOX5AP G A 1.13E−02 0.73 0.432 0.514 82 45 181 96 136 40
genes
2 - Priority rs9670531 13 31321069 ALOX5AP A G 1.13E−02 0.73 0.432 0.514 82 41 181 96 136 40
genes
1 - Priority rs2487896 10 100302380 HPSE2 G A 1.29E−02 0.65 0.130 0.186 6 6 92 55 301 119
variants
0 - Priority rs3135391 6 32410987 HLA-DRA G A 1.44E−02 0.70 0.203 0.268 20 10 122 77 257 94
variants,
Predictive
Model
2 - Priority kgp26271158 6 32823393 PSMB9 G A 1.47E−02 0.29 0.008 0.025 0 0 6 9 393 172
genes
1 Priority rs3135388 6 32413051 G A 1.66E−02 0.70 0.203 0.267 20 10 122 76 257 94
variants
2 - Priority kgp11281589 7 1941003 MADIL1 A G 1.76E−02 1.48 0.246 0.184 19 5 155 55 219 117
genes
1 - Priority rs17575455 2 76424220 C A 1.94E−02 0.73 0.319 0.390 42 26 170 89 186 66
variants
1 - Priority rs947603 10 95249605 A G 2.65E−02 1.42 0.241 0.182 22 8 148 50 228 123
variants
(Note:
Odds Ratio >1 = Minor Allele is associated with Response, Odds Ratio <1 = Minor Allele Associated with Non-Response)
indicates data missing or illegible when filed
TABLE 29
Extreme Response SNPs
Galx cohort Forte cohort
EXTREME PHENOTYPE Odds Odds
Major Minor P-value Ratio Minor Allele Allele Freq. P-value Ratio Minor Allele Allele Freq.
Prioritized Allele Allele ((Armitage Minor Freq. (Non- ((Armitage (Minor Freq. (Non-
Variants Nam(Minore Chromosome Position Gene(s) (d) (D) Test) Allele) (Responders) Responders) Test) Allele) (Responders) (Responders)
0-Priority-Model kgp6214351 11 75546591 UVRAG A G 2.44E−03 0.20 0.010 0.128 3.36E−05 0.12 0.028 0.171
0-Priority-Model rs759458 2 65245365 SLCLA4 G A 4.44E−05 3.31 0.356 0.157 4.89E−02 1.86 0.364 0.229
rs7845274 8 72411302 C A 1.15E−03 0.42 0.212 0.390 1.38E−02 0.45 0.170 0.314
kgp3984567 4 40379690 G A 9.80E−05 0.34 0.379 0.587 6.90E−03 0.42 0.438 0.614
kgp11580695 10 3896633 G A 5.50E−05 0.18 0.053 0.212 1.02E−01 0.50 0.073 0.143
kgp10948564 20 44082511 G C 3.35E−03 0.41 0.197 0.331 4.38E−03 0.41 0.146 0.314
rs197523 21 19337261 CHODL G A 6.01E−05 2.89 0.402 0.186 4.34E−02 1.86 0.371 0.229
kgp12371757 9 19458272 G A 4.17E−05 0.21 0.068 0.244 6.77E−02 0.49 0.112 0.200
kgp9627338 17 90155 RPHIAL A G 2.55E−03 0.36 0.083 0.221 2.27E−04 0.23 0.108 0.286
rs7850 2 65249922 SLC1A4 C A 5.39E−07 8.99 0.212 0.035 2.42E−01 1.74 0.140 0.086
kgp7189498 2 65250677 SLC1A4 G C 8.57E−07 8.77 0.215 0.037 2.08E−01 1.82 0.145 0.086
kgp10788130 12 13898652 GRIN2B G A 3.62E−03 Zero 0.000 0.070 1.48E−04 0.08 0.011 0.114
kgp7242489 2 65250541 CLC1A4 A T 6.51E−07 8.88 0.212 0.005 2.42E−01 1.74 0.140 0.086
kgp7077322 4 164661252 A C 1.82E−03 0.13 0.015 0.100 3.59E−04 0.16 0.034 0.157
rs7348267 20 44084386 G A 3.35E−03 0.41 0.197 0.331 8.93E−03 0.44 0.146 0.300
kgp7121374 2 65246727 SLC1A4 A G 6.51E−07 8.88 0.212 0.035 3.18E−01 1.57 0.148 0.100
kgp4127859 6 32434181 A G 1.28E−04 3.79 0.235 0.076 2.67E−02 2.89 0.193 0.086
kgp8107491 6 164295151 G A 7.53E−04 0.43 0.348 0.541 2.00E−02 0.50 0.341 0.500
rs16895510 6 164319963 G A 1.81E−04 0.33 0.162 0.353 9.67E−02 0.55 0.182 0.271
rs6022205 20 44082799 C A 4.36E−03 0.41 0.203 0.335 9.99E−03 0.44 0.148 0.300
kgp11768535 11 27270451 G A 1.14E−03 2.52 0.500 0.337 1.79E−03 2.75 0.472 0.257
rs502530 6 145584096 C A 2.10E−05 0.19 0.015 0.070 6.23E−05 Zero 0.000 0.086
rs1478682 11 27335009 G A 7.52E−03 2.57 0.485 0.314 2.93E−03 2.60 0.449 0.243
kgp1124492 1 105554880 G A 9.05E−02 0.26 0.068 0.194 6.10E−02 0.41 0.057 0.129
kgp11843177 11 27316568 A G 4.45E−02 2.69 0.394 0.218 1.55E−02 2.28 0.371 0.214
kgp11467007 5 172750436 STC2 G A 1.49E−03 0.17 0.023 0.128 1.24E−03 0.22 0.051 0.171
rs190295 10 121436362 BAG3 G A 3.59E−03 0.35 0.114 0.302 6.11E−03 0.41 0.182 0.343
rs11029892 11 27269546 G A 5.83E−02 2.63 0.417 0.244 1.11E−02 2.36 0.393 0.229
rs9913349 17 68260070 A G 2.13E−02 2.39 0.318 0.169 2.74E−02 2.10 0.371 0.219
kgp5680955 6 164297121 G A 6.88E−02 0.43 0.288 0.483 2.10E−02 0.51 0.301 0.457
kgp6236949 2 60301030 A G 1.30E−02 0.45 0.280 0.465 6.45E−02 0.56 0.242 0.357
rs196343 10 12147957 BAG3 G A 4.43E−03 0.36 0.114 0.300 5.34E−03 0.40 0.180 0.343
rs7217872 17 88988 RPH3AL G A 3.72E−04 0.37 0.083 0.215 3.34E−04 0.24 0.112 0.286
kgp4634875 7 117404583 THSD7A G A 3.67E−02 2.01 0.545 0.378 1.15E−02 0.46 0.416 0.588
kgp4418535 6 32431558 C A 2.45E−02 2.58 0.227 0.076 2.93E−02 2.84 0.191 0.086
rs1079303 11 27269598 A G 1.14E−03 2.52 0.500 0.337 2.32E−03 2.66 0.466 0.257
rs10501082 11 27270978 G A 1.14E−03 2.52 0.500 0.337 2.32E−03 2.66 0.466 0.257
rs6718758 2 60328802 C A 6.94E−03 0.53 0.311 0.471 9.16E−03 0.44 0.253 0.414
rs7725112 5 173996604 G A 2.09E−02 3.94 0.312 0.070 3.76E−02 2.58 0.197 0.086
kgp4734301 11 27315427 A G 5.37E−02 2.64 0.394 0.221 1.55E−02 2.28 0.371 0.214
rs11029928 11 27319188 G A 5.37E−02 2.64 0.394 0.221 1.55E−02 2.28 0.371 0.214
rs7948420 11 27276450 A G 6.04E−03 0.23 0.205 0.424 6.96E−01 0.46 0.326 0.514
kgp18432055 9 108536422 TMEM38B A T 5.20E−04 3.51 0.205 0.065 8.25E−03 4.81 0.163 0.043
rs10954782 8 31076640 A G 3.11E−02 1.66 0.515 0.390 2.07E−03 0.40 0.371 0.586
kgp8599417 6 168319353 G A 2.53E−04 0.34 0.159 0.345 9.67E−02 0.55 0.182 0.271
rs7028906 9 1084530368 G A 1.23E−04 4.13 0.212 0.058 1.93E−02 4.37 0.140 0.043
kgp9078300 2 23615634 KLHL29 A G 1.83E−02 2.18 0.208 0.110 9.97E−04 4.88 0.253 0.071
rs7563131 2 65248271 SLC1A4 G A 8.76E−07 9.70 0.200 0.029 4.39E−08 1.42 0.156 0.100
rs7928078 13 27271285 A G 1.84E−03 2.44 0.492 0.337 2.32E−09 2.66 0.466 0.257
rs1157449 8 73277404 G A 4.28E−03 0.37 0.106 0.227 2.48E−02 0.40 0.073 0.171
kgp9884626 2 206731028 A G 4.15E−03 Zero 0.000 0.058 5.43E−03 Zero 0.000 0.043
rs11083404 18 28087536 A G 1.85E−01 1.45 0.273 0.209 2.86E−05 5.40 0.388 0.114
rs9579566 13 30980265 G A 1.39E−02 Zero 0.000 0.081 7.80E−03 0.17 0.017 0.086
kgp5292386 5 159424526 C A 3.96E−03 0.21 0.030 0.116 2.60E−02 0.21 0.017 0.071
rs7496458 15 25718875 G A 2.61E−02 2.10 0.212 0.122 1.28E−03 4.21 0.270 0.100
kgp5017029 17 48868049 WNT3 G A 9.50E−03 0.22 0.023 0.100 1.37E−03 0.11 0.011 0.086
kgp1355977 6 145373380 G A 3.29E−02 0.21 0.015 0.064 6.23E−05 Zero 0.000 0.086
rs11029907 11 27295271 C G 1.84E−03 2.44 0.492 0.337 2.49E−03 2.64 0.466 0.257
kgp6008357 11 27276484 G A 1.14E−03 2.52 0.500 0.337 3.19E−03 2.56 0.461 0.257
kgp11077373 5 172750120 STC2 C A 3.30E−00 0.22 0.030 0.129 1.24E−03 0.22 0.051 0.171
kgp3202939 12 13859947 ORIN2B G A 1.36E−02 0.12 0.008 0.070 1.12E−04 0.07 0.011 0.138
kgp11686146 2 142745416 LRP1B G A 8.92E−04 0.12 0.015 0.122 3.01E−02 0.29 0.034 0.100
rs11085044 19 3890641 ATCAY G A 1.87E−04 0.40 0.227 0.453 3.17E−01 0.74 0.236 0.300
kgp3730395 9 91520540 C A 1.01E−02 0.52 0.288 0.430 4.63E−04 0.36 0.287 0.529
rs2175121 9 108497519 TMENG8B A G 8.41E−04 3.26 0.205 0.070 7.57E−03 4.88 0.165 0.043
kgp487328 22 26134006 G A 6.03E−05 0.19 0.061 0.215 5.89E−01 0.77 0.079 0.100
kgp1912531 2 157250215 THSD7B A G 1.22E−03 2.73 0.250 0.105 1.23E−02 2.81 0.244 0.086
kgp9450430 20 44085460 A G 6.01E−03 0.44 0.197 0.326 1.74E−02 0.47 0.146 0.286
kgp2391411 2 43425645 G A 7.19E−04 0.39 0.182 0.360 5.85E−03 0.47 0.236 0.429
rs10816302 9 108486533 TMEM38B G A 8.41E−04 3.26 0.205 0.070 8.25E−03 4.81 0.163 0.043
rs7020402 9 108530638 TMEM38B A G 8.41E−04 3.26 0.205 0.070 8.25E−03 4.81 0.163 0.043
rs1979993 9 108534505 TMEM38B A G 8.41E−04 3.26 0.205 0.070 8.25E−03 4.81 0.136 0.043
rs1979992 9 108535330 TMEM38B A G 8.41E−04 3.26 0.205 0.070 8.25E−03 4.81 0.136 0.043
rs6032209 20 44087073 A G 6.33E−03 0.45 0.208 0.341 2.28E−02 0.49 0.152 0.286
kgp7521990 1 105666878 C A 4.53E−03 0.34 0.069 0.186 8.31E−03 0.30 0.067 0.171
kgp2451249 1 223872873 A G 3.08E−03 3.43 0.152 0.052 1.55E−02 3.68 0.174 0.057
kgp8796185 1 223716508 CAPN8 G A 4.13E−03 3.32 0.144 0.047 2.22E−02 3.18 0.180 0.071
rs2241883 2 88424066 FABP1 A G 1.18E−03 0.43 0.273 0.453 4.71E−02 0.54 0.275 0.400
rs343037 12 66260924 HMGA2 G A 5.81E−03 2.59 0.182 0.070 1.04E−02 3.25 0.222 0.071
rs1894701 3 174931730 NAALADL2 A C 2.64E−03 2.14 0.547 0.378 1.97E−02 0.50 0.438 0.600
kgp18525257 9 108499628 TMEM38B G A 1.10E−03 3.27 0.197 0.070 8.25E−03 4.81 0.163 0.043
kgp18379774 9 108504407 TMEM38B G A 1.10E−03 2.27 0.197 0.070 8.25E−03 4.81 0.163 0.043
rs10512340 9 108511163 TMEM38B G A 1.10E−03 3.27 0.197 0.070 8.25E−03 4.81 0.163 0.043
rs10125298 9 108515598 C A 1.10E−03 3.27 0.197 0.070 8.25E−03 4.81 0.163 0.043
kgp759150 4 40385906 G A 5.21E−03 2.09 0.583 0.419 7.28E−04 3.23 0.528 0.314
rs10124492 9 108527455 TMEM38B T A 1.25E−03 3.14 0.200 0.070 7.57E−03 4.88 0.165 0.043
kgp3812034 2 43427044 A G 9.26E−04 0.40 0.189 0.365 6.74E−03 0.47 0.238 0.429
rs5024722 7 141858684 A G 2.52E−02 0.52 0.189 0.297 1.52E−03 0.34 0.136 0.314
rs11691553 2 60303554 C A 5.69E−03 0.52 0.323 0.488 2.06E−02 0.48 0.284 0.429
kgp11453406 10 121435955 BAG3 C A 4.93E−04 0.40 0.174 0.372 3.47E−02 0.49 0.233 0.357
rs196341 10 121416611 BAG3 G A 7.33E−04 0.41 0.177 0.371 2.73E−02 0.48 0.227 0.357
rs10203396 2 60305110 A G 5.80E−03 0.52 0.326 0.488 2.22E−02 0.48 0.287 0.429
rs7579987 2 60307009 G C 5.80E−03 0.52 0.326 0.488 2.22E−02 0.48 0.287 0.429
rs7862565 9 108592419 G A 1.06E−03 3.47 0.182 0.058 2.11E−02 3.52 0.163 0.057
kgp11514107 2 65247253 SLCIA4 G A 8.67E−06 6.07 0.212 0.047 2.42E−01 1.74 0.140 0.086
rs4822644 22 26134163 G A 8.28E−05 0.21 0.068 0.227 5.56E−01 0.76 0.090 0.114
rs2136408 9 108497654 TMEM38B A C 9.59E−04 3.22 0.205 0.071 9.89E−03 4.66 0.163 0.044
rs1545223 2 28423510 FABP1 A G 1.59E−03 0.44 0.277 0.453 4.71E−02 0.54 0.275 0.400
rs17329014 2 60299921 G A 7.67E−03 0.50 0.235 0.378 1.94E−02 0.48 0.185 0.229
rs2058742 17 70040547 C A 5.12E−03 2.13 0.333 0.192 1.26E−02 2.38 0.360 0.200
kgp4420791 12 89819166 POC1B G A 5.14E−02 0.24 0.015 0.058 2.69E−05 0.04 0.006 0.114
kgp7714238 6 145587514 G A 2.10E−02 0.19 0.015 0.070 5.03E−04 0.05 0.006 0.086
rs13394010 2 60302746 A G 6.13E−03 0.52 0.326 0.488 2.22E−02 0.48 0.287 0.429
kgp7924485 2 60292120 A G 2.04E−02 0.50 0.152 0.262 4.46E−03 0.36 0.097 0.243
kgp8174785 1 110053148 G C 6.72E−03 0.51 0.258 0.413 1.26E−02 0.39 0.236 0.371
kgp10090631 7 11754881 THSD7A A G 3.50E−02 1.67 0.447 0.327 3.08E−03 2.59 0.539 0.338
kgp1683448 9 108449079 A G 2.68E−04 4.49 0.177 0.047 3.67E−02 3.60 0.129 0.044
kgp8777935 6 139004920 A G 8.38E−03 1.93 0.424 0.279 1.05E−02 2.08 0.478 0.286
rs16930057 8 63609122 G A 1.04E−04 0.27 0.091 0.273 1.87E−01 0.61 0.148 0.214
kgp7181058 14 98385698 G A 2.56E−03 Zero 0.000 0.064 1.09E−01 Zero 0.000 0.014
kgp11711524 9 108546438 G A 1.66E−03 3.14 0.192 0.070 8.25E−03 4.81 0.163 0.043
kgp6505544 7 71953948 G A 1.89E−03 3.08 0.205 0.087 1.42E−02 3.26 0.202 0.071
rs73011 17 68258446 G A 5.73E−03 2.32 0.258 0.154 4.39E−02 2.07 0.320 0.200
kgp355027 11 115964147 A G 9.27E−03 0.41 0.106 0.215 2.70E−03 0.31 0.098 0.243
kgp767200 5 3221345 A G 2.83E−05 4.41 0.262 0.094 1.10E−01 2.06 0.184 0.103
kgp5908616 2 60329823 A C 1.62E−02 0.58 0.326 0.471 8.04E−03 0.43 0.261 0.429
kgp3205849 10 121531725 INPP5P A G 1.63E−04 0.33 0.129 0.331 1.15E−01 0.59 0.195 0.286
kgp9220791 2 60309952 C G 5.80E−03 0.52 0.326 0.488 2.56E−02 0.49 0.290 0.429
kgp3267884 9 14639380 ZDHHC21 G A 1.21E−03 0.41 0.212 0.384 1.03E−01 0.59 0.202 0.300
rs13002663 2 145220163 ZEBZZEB2 G A 1.08E−02 0.55 0.318 0.471 3.61E−03 0.40 0.298 0.486
kgp8767692 15 66333821 MEGF11 G A 2.29E−02 0.24 0.023 0.081 6.05E−04 0.09 0.011 0.100
kgp28532436 15 62968836 TLN2 G A 9.69E−04 15.18 0.076 0.006 2.23E−02 Infinity 0.067 0.000
rs9346979 6 164309479 G A 1.23E−03 0.45 0.295 0.483 4.65E−02 0.56 0.309 0.443
rs714342 11 110807983 A C 3.45E−03 2.13 0.447 0.291 4.88E−02 1.95 0.478 0.357
kgp8869954 2 135163015 MGAT5 G A 3.62E−03 0.22 0.030 0.128 3.67E−03 0.25 0.051 0.357
kgp2709692 18 3000808 LPIN2 C A 1.29E−02 0.21 0.015 0.064 2.95E−04 Zero 0.000 0.071
rs10510774 3 54919351 CACNA2O3 A G 7.25E−04 0.23 0.053 0.176 1.08E−01 0.46 0.068 0.129
kgp8169636 18 29206763 B4GALT6 G A 1.12E−02 0.32 0.045 0.134 1.26E−02 0.24 0.022 0.100
kgp3592828 5 173993252 C A 6.50E−04 2.56 0.341 0.169 1.87E−02 2.49 0.281 0.143
kgp11010680 15 25717889 A G 5.83E−02 1.87 0.205 0.128 1.08E−03 4.31 0.273 0.100
rs1387768 5 173993165 A G 7.86E−04 2.53 0.341 0.171 1.65E−02 2.54 0.384 0.143
kgp11627530 14 78954642 NRXN3 A G 1.79E−02 0.32 0.038 0.116 1.37E−04 0.20 0.039 0.186
kgp10404633 9 138136993 G A 1.73E−03 8.40 0.083 0.012 2.76E−02 7.45 0.090 0.014
kgp8372910 9 138138723 G A 1.72E−03 8.40 0.083 0.012 2.76E−02 7.45 0.090 0.014
kgp11206433 3 54928104 CACNA2D3 G A 8.29E−04 0.24 0.053 0.174 1.02E−01 0.45 0.067 0.129
rs11136970 8 604262 A C 3.39E−02 1.72 0.333 0.221 6.18E−03 2.40 0.432 0.243
kgp9795733 15 88117171 C A 1.33E−03 0.30 0.069 0.208 2.58E−02 0.45 0.091 0.200
rs2934491 16 84905542 CRISPLD2 G A 7.45E−03 0.52 0.295 0.448 9.75E−03 0.45 0.275 0.443
kgp9368119 7 11707419 THSD7A A G 2.23E−02 0.58 0.379 0.512 1.08E−02 0.44 0.298 0.457
rs4709792 6 164316375 G A 1.21E−03 0.45 0.288 0.477 4.65E−02 0.56 0.309 0.443
rs17400575 2 60295736 A C 7.67E−03 0.50 0.235 0.378 2.48E−02 0.50 0.191 0.329
kgp10152733 9 102462735 TMEMG8B G A 1.50E−03 3.01 0.205 0.076 8.25E−03 4.81 0.163 0.043
kgp12426624 3 54926209 CACNA2D3 C A 1.90E−03 0.27 0.061 0.174 4.78E−02 0.39 0.067 0.143
kgp55646 10 121262886 RGS10 G A 1.09E−02 0.53 0.265 0.407 7.63E−03 0.43 0.233 0.400
kgp10922969 6 80260277 G A 7.52E−02 0.50 0.076 0.141 1.38E−04 0.13 0.028 0.157
kgp7331172 18 66533114 CCDC102B A G 1.95E−05 4.29 0.273 0.093 1.70E−01 1.79 0.185 0.114
kgp6666134 10 129386358 T A 7.27E−03 2.10 0.295 0.163 1.00E−02 2.58 0.320 0.157
kgp6603796 16 84910892 CRISPLD2 G A 7.24E−03 0.50 0.259 0.419 8.24E−03 0.45 0.253 0.429
kgp9018750 6 164312470 A G 1.23E−03 0.45 0.295 0.413 5.29E−02 0.57 0.313 0.443
rs58341 6 132160455 ENPP1 A G 1.05E−03 2.26 0.462 0.279 8.21E−02 1.67 0.466 0.343
kgp4096263 15 7033438 A G 4.37E−04 3.81 0.195 0.059 4.01E−02 3.10 0.149 0.057
kgp5150037 2 65255764 A G 2.59E−05 4.31 0.250 0.070 2.62E−01 1.61 0.176 0.116
rs423239 9 92856946 G A 3.11E−03 2.61 0.220 0.093 1.50E−02 3.08 0.213 0.086
rs143092 12 66250940 HMGA2 C A 9.60E−03 2.44 0.174 0.070 1.23E−02 3.22 0.213 0.071
kgp7176233 5 117621827 C A 2.69E−03 2.57 0.242 0.110 7.02E−02 1.98 0.275 0.171
kgp3218351 11 110802128 G A 3.59E−03 2.16 0.432 0.279 4.32E−02 1.95 0.455 0.329
kgp10564659 1 223713531 G A 7.40E−03 3.09 0.136 0.047 2.66E−02 3.08 0.176 0.071
PI_M_061510_11_106_M 11 27308202 D I 5.93E−05 0.32 0.205 0.419 1.14E−02 0.48 0.354 0.529
kgp6023196 17 68271273 A C 3.52E−03 2.28 0.311 0.169 2.11E−02 1.81 0.360 0.243
kgp1056892 20 44087774 C G 1.99E−02 0.50 0.205 0.314 1.60E−02 0.46 0.125 0.271
rs84482 15 55418825 A G 1.53E−04 5.20 0.152 0.035 7.88E−02 2.89 0.119 0.043
kgp6737096 15 66299395 MEGF11 G A 3.55E−02 0.31 0.030 0.087 6.05E−04 0.09 0.011 0.100
kgp6076976 1 105663380 A T 2.57E−03 0.27 0.053 0.161 3.03E−02 0.35 0.062 0.143
rs9597492 13 57657550 G A 2.81E−03 1.98 0.470 0.291 1.44E−02 2.06 0.489 0.271
rs419132 6 32210799 A G 4.24E−05 2.62 0.523 0.271 1.05E−01 1.66 0.381 0.271
kgp29794723 10 18397332 A G 1.33E−02 0.18 0.015 0.076 2.55E−03 0.11 0.011 0.086
kgp6091118 17 42879640 WNT3 A G 1.28E−02 0.27 0.030 0.110 7.80E−03 0.17 0.017 0.086
kgp10351364 8 103604706 G A 5.14E−03 2.02 0.559 0.393 3.01E−03 2.63 0.523 0.334
rs9376361 6 139005406 A G 2.74E−03 2.07 0.453 0.285 4.52E−02 1.76 0.477 0.329
kgp3991733 1 105671167 T A 4.36E−02 0.40 0.076 0.176 2.17E−03 0.26 0.067 0.186
rs6687976 1 105674536 C A 1.36E−02 0.40 0.076 0.176 3.12E−03 0.26 0.067 0.186
2-Priority Genes rs6110157 20 14055947 MACROD2 A G 2.18E−02 0.53 0.215 0.331 7.82E−03 0.45 0.176 0.343
(extreme)
2-Priority Genes kgp4011779 10 100454360 HPSE2 G A 2.48E−02 0.25 0.023 0.081 2.30E−02 Zero 0.000 0.029
(extreme)
0-Priority-Model rs16886004 7 78021500 MAG12 A G 3.05E−03 2.04 0.189 0.100 9.21E−03 3.64 0.202 0.071
2-Priority Genes kgp3496814 13 31336379 ALOX5AP C A 2.87E−02 0.60 0.304 0.523 2.60E−04 0.37 0.423 0.671
(extreme)
0-Priority-Model, rs10162089 13 31316738 ALOX5AP G A 5.86E−03 1.93 0.561 0.399 1.29E−03 2.32 0.460 0.257
Priority Genes
2-Priority Genes rs3885907 13 34314455 ALOX5AP A C 1.59E−02 1.73 0.523 0.372 2.74E−03 2.56 0.455 0.243
(extreme)
0-Priority-Model rs1894408 6 32186833 C G 8.94E−02 1.50 0.392 0.297 2.63E−03 2.85 0.420 0.229
0-Priority-Model kgp3817856 6 32744440 G A 3.61E−02 0.58 0.369 0.483 9.23E−03 0.45 0.369 0.543
2-Priority Genes rs17238927 13 31332391 ALOX5AP G A 4.20E−02 0.15 0.008 0.047 2.30E−02 Zero 0.000 0.029
(extreme)
2-Priority Genes rs9671124 13 31324253 ALOX5AP G A 2.25E−02 1.69 0.561 0.424 1.97E−03 2.57 0.494 0.271
(extreme)
2-Priority Genes rs4769060 13 31337877 ALOX5AP A G 3.03E−02 1.69 0.500 0.378 3.71E−03 2.43 0.456 0.257
(extreme)
0-Priority-Model kgp24415534 2 174156875 G A 4.38E−02 0.15 0.008 0.047 2.30E−02 Zero 0.000 0.029
2-Priority-Genes rs4975692 13 31323342 ALOX5AP G A 2.25E−02 1.69 0.561 0.424 2.31E−03 2.55 0.459 0.371
(extreme)
2-Priority Genes rs11147439 13 31325643 ALOX5AP C A 1.83E−02 0.57 0.364 0.500 8.86E−03 0.48 0.421 0.614
(extreme)
2-Priority Genes kpg3276689 10 100396003 HPSE2 C A 4.39E−02 1.50 0.192 0.106 3.64E−02 2.48 0.213 0.100
(extreme)
2-Priority Genes kpg301921 20 14017077 MACROD2 A G 4.20E−02 0.34 0.031 0.095 2.65E−02 0.29 0.028 0.100
(extreme)
2-Priority Genes rs3801277 13 31318308 ALOX5AP C A 1.63E−02 0.57 0.371 0.512 1.25E−02 0.49 0.433 0.614
(extreme)
2-Priority Genes kgp5440506 13 31320543 ALOX5AP G A 1.74E−02 0.57 0.362 0.500 1.14E−02 0.49 0.427 0.618
(extreme)
2-Priority Genes rs9671182 13 31321134 ALOX5AP C G 1.93E−02 0.57 0.371 0.506 1.38E−02 0.50 0.433 0.614
(extreme)
0-Priority-Model kgp8110667 22 32716792 G A 9.44E−03 Infinity 0.031 0.000 1.15E−01 Infinity 0.034 0.000
2-Priority-Genes rs4254166 13 31322949 ALOX5AP A G 2.51E−02 0.59 0.371 0.500 1.05E−02 0.49 0.427 0.614
(extreme)
2-Priority Genes rs4356336 13 31319546 ALOX5AP A G 2.03E−02 0.58 0.371 0.506 1.38E−02 0.50 0.433 0.614
(extreme)
2-Priority Genes rs1002051 10 78921392 KCNMA1 G A 1.50E−02 0.29 0.038 0.110 2.78E−02 0.38 0.067 0.157
(extreme)
2-Priority Genes rs10278591 7 1921362 MAD1L1 G A 1.63E−02 1.95 0.303 0.186 4.33E−02 2.15 0.264 0.143
(extreme)
2-Priority Genes rs4360791 13 31318020 ALOX5AP G A 1.79E−02 0.57 0.379 0.517 2.10E−02 0.53 0.444 0.614
(extreme)
2-Priority Genes kgp2715823 13 31320249 ALOX5AP G A 2.51E−02 0.59 0.371 0.500 1.38E−02 0.50 0.433 0.614
(extreme)
2-Priority Genes rs9670531 13 31321069 ALOX5AP A G 2.51E−02 0.59 0.371 0.500 1.38E−02 0.50 0.433 0.614
(extreme)
2-Priority Genes rs9315047 13 31321289 ALOX5AP A T 2.51E−02 0.59 0.371 0.500 1.38E−02 0.50 0.433 0.614
(extreme)
2-Priority Genes rs4584668 13 31319553 ALOX5AP A T 2.60E−02 0.59 0.371 0.500 1.38E−02 0.50 0.433 0.614
(extreme)
2-Priority Genes rs9508832 13 31314264 ALOX5AP G A 2.16E−03 1.73 0.492 0.360 1.08E−02 2.21 0.410 0.229
(extreme)
1-Priority Variant rs2487896 10 100802380 HPSE2 G A 1.30E−01 0.60 0.106 0.171 1.66E−03 0.33 0.118 0.286
(extreme)
2-Priority Genes kgp7117398 7 1915282 MAD1L1 C A 2.26E−02 1.88 0.303 0.192 4.33E−02 2.15 0.264 0.143
(extreme)
1-Priority Variant rs10988087 9 131443671 A G 2.31E−01 0.48 0.030 0.059 1.01E−03 0.18 0.028 0.143
(extreme)
0-Priority-Model kgp6599438 20 40843626 PTPRT G A 6.74E−03 Infinity 0.000 0.052 1.57E−01 0.36 0.022 0.057
0-Priority-Model, rs3135391 6 32410987 HLA-DRA G A 6.04E−02 0.58 0.182 0.273 2.79E−02 0.50 0.197 0.329
Priority Variant
1-Priority Variant rs1573706 20 40921149 PTPRT G A 6.38E−01 0.87 0.182 0.203 4.80E−04 0.28 0.107 0.286
(extreme)
2-Priority Genes kgp4370912 10 78918297 KCNMA1 C A 3.18E−02 0.53 0.038 0.100 2.78E−02 0.38 0.067 0.157
(extreme)
1-Priority Variant rs3135388 6 32412051 G A 6.92E−02 0.59 0.182 0.271 2.79E−02 0.50 0.192 0.329
(extreme)
0-Priority-Model kgp7747883 18 74804250 MBP G A 2.44E−01 0.76 0.364 0.430 3.55E−02 0.53 0.290 0.429
1-Priority Variant rs6097801 20 52767434 G A 8.23E−01 0.93 0.136 0.145 5.74E−01 0.41 0.090 0.243
(extreme)
Combined
EXTREME PHENOTYPE Odds Minor Allele DD Dd dd
Major Minor P-value Ratio Allele Freq. (Re- DD (Non- (Re- Dd (Non- (Re- dd (non-
Prioritized Chro- Allele Allele (Armitage (Minor Freq. (Re- (NonRe- spond- respond- spond- respond- spond- respond-
Variants Name mosome Position Gene(s) (d) (D) Test) Allele) sponders) sponders) ers) ers) ers) ers) ers) ers)
0-Priority-Model kgp6214351 11 75546691 UVRAG A G 9.09E−07 0.17 0.029 0.140 0 1 9 32 145 68
0-Priority-Model rs759458 2 65245365 SLC1A4 G A 2.92E−06 2.64 0.360 0.178 20 3 71 37 63 81
rs7844274 8 72411302 C A 3.82E−06 0.40 0.188 0.368 4 18 50 53 100 50
kgp3984567 4 40379690 G A 4.36E−06 0.40 0.413 0.595 21 36 86 72 48 13
kgp11580695 10 3896625 G A 5.42E−06 0.28 0.065 0.192 0 4 20 38 135 78
kgp10948564 20 44082511 G C 6.43E−06 0.37 0.168 0.326 4 8 41 63 107 50
rs197523 21 19337261 CHODL G A 7.05E−06 2.39 0.184 0.198 26 5 67 38 62 78
kgp12371757 9 19458272 G A 7.23E−06 0.33 0.094 0.231 0 6 29 44 126 71
kgp9627338 17 90155 RPH3AL A G 8.19E−06 0.34 0.097 0.240 1 7 28 44 125 70
rs7850 2 65249922 SLC1A4 C A 8.39E−06 4.22 0.121 0.050 3 0 47 12 105 109
kgp7189498 2 65250677 SLC1A4 G C 8.87E−06 4.23 0.175 0.051 3 0 47 12 101 105
kgp10788130 12 13898682 GRINZB G A 9.66E−06 0.07 0.006 0.083 0 1 2 18 153 102
kgp7242489 2 65250561 SLC1A4 A T 9.71E−06 4.19 0.171 0.050 3 0 47 12 105 108
kgp7077322 4 164561252 A C 1.04E−05 0.18 0.026 0.117 0 0 8 28 146 92
rs7348267 20 44084386 G A 1.10E−05 0.39 0.168 0.322 4 8 44 62 107 51
kgp7121374 2 65246727 SLC1A4 A G 1.20E−05 3.99 0.175 0.054 3 0 48 13 103 107
kgp4127859 6 32434481 A G 1.21E−05 3.38 0.211 0.079 5 0 55 19 94 102
kgp8107491 6 164295151 G A 1.21E−05 0.45 0.344 0.529 17 32 72 64 65 25
rs16895510 6 164319963 G A 1.30E−05 0.40 0.173 0.331 3 11 47 58 103 52
rs6032205 20 44082799 C A 1.43E−05 0.39 0.171 0.325 4 8 44 62 104 50
kgp11768533 11 27270451 G A 1.54E−05 2.37 0.484 0.314 32 5 85 66 37 50
rs502530 6 145584096 C A 1.56E−05 0.07 0.006 0.074 0 0 2 18 153 103
rs1478682 11 27335009 G A 1.67E−05 2.34 0.464 0.293 31 4 81 63 42 54
kgp1124492 1 105554880 G A 1.74E−05 0.28 0.062 0.175 0 2 19 38 135 80
kgp11843177 11 27316568 A G 1.82E−05 2.43 0.381 0.217 20 2 78 48 57 70
kgp11467002 5 172750436 STC2 G A 1.83E−05 0.24 0.039 0.140 0 2 12 30 143 89
rs196295 10 121436362 BAG3 G A 1.86E−05 0.42 0.153 0.314 4 15 59 46 111 60
rs11029892 11 27269546 G A 1.89E−05 2.41 0.403 0.240 22 2 81 54 52 65
rs9913349 17 68260070 A G 1.89E−05 2.45 0.348 0.186 15 5 78 33 62 81
kgp5680955 6 164297121 G A 1.90E−05 0.46 0.295 0.475 13 27 65 61 76 33
kgp6236949 2 60301030 A G 1.93E−05 0.45 0.258 0.434 8 25 64 55 83 41
rs196343 10 121417957 BAG3 G A 2.00E−05 0.42 0.152 0.318 4 15 39 45 112 60
rs7217672 17 88988 RPH3AL G A 2.04E−05 0.36 0.100 0.236 1 7 29 43 125 71
kgp4634873 7 11704583 THSD7A G A 2.15E−05 2.18 0.368 0.388 48 16 80 61 27 43
kgp4418535 6 32431558 C A 2.15E−05 3.26 0.206 0.079 5 0 54 19 96 102
rs1079303 11 27269598 A G 2.19E−05 2.33 0.481 0.314 32 5 85 66 38 50
rs10501082 11 27270978 G A 2.19E−05 2.33 0.481 0.314 32 5 85 66 38 50
rs6718758 2 60328802 C A 2.22E−05 0.46 0.277 0.455 10 27 66 56 79 38
rs7225112 5 173996604 G A 2.22E−05 3.27 0.203 0.074 5 1 53 16 97 104
kgp4734301 11 27315427 A G 2.24E−05 2.40 0.381 0.219 20 2 78 49 57 70
rs11029928 11 27319188 G A 2.24E−05 2.40 0.381 0.219 20 2 78 49 57 70
rs7948420 11 27276450 A G 2.24E−05 0.46 0.274 0.450 12 24 61 61 82 36
kgp18432055 9 108536427 TMEM383 A T 2.33E−05 3.61 0.181 0.058 5 0 46 14 104 106
rs10954782 8 31076640 A G 2.36E−05 2.11 0.591 0.397 53 18 74 60 28 43
kgp8599417 6 164319353 G A 2.37E−05 0.40 0.172 0.324 3 10 47 57 104 52
rs7028906 9 108450368 G A 2.57E−05 3.74 0.171 0.054 4 0 45 13 106 108
kgp9078300 2 23615634 KLHL39 A G 2.65E−05 2.95 0.234 0.099 6 1 60 22 88 98
rs7563131 2 65248271 SLC1A4 G A 2.85E−05 3.90 0.163 0.050 3 0 44 12 106 108
rs7928076 11 27271285 A G 3.04E−05 2.30 0.477 0.314 31 3 85 66 38 50
rs1157449 8 73277404 G A 3.05E−05 0.34 0.087 0.211 1 4 25 43 129 74
kgp9884626 2 206731028 A G 3.08E−05 Zero 0.000 0.054 0 0 0 13 154 108
rs11083404 18 28087516 A G 3.14E−05 2.41 0.339 0.182 16 3 73 38 66 20
rs9579566 13 30980265 G A 3.19E−05 0.11 0.010 0.083 0 1 3 18 152 102
kgp5292386 5 159424526 C A 3.22E−05 0.18 0.023 0.103 0 0 7 25 148 96
rs7496451 15 25718875 G A 3.25E−05 2.89 0.245 0.116 4 0 68 28 83 93
kgp5017029 17 44868049 WNT3 G A 3.26E−05 0.15 0.016 0.096 0 1 5 21 149 98
kgp1355977 6 145573380 G A 3.36E−05 0.08 0.006 0.070 0 0 2 17 153 104
rs11029907 11 27295271 C G 3.27E−05 2.29 0.477 0.314 31 5 84 66 38 50
kgp6038357 11 27276484 G A 3.31E−05 2.27 0.477 0.314 32 5 84 66 39 50
kgp11077373 5 172750120 STC2 C A 3.32E−05 0.26 0.042 0.142 0 2 13 30 142 88
kgp3202939 12 13859947 GRIN2B G A 3.33E−05 0.11 0.010 0.083 0 1 3 18 150 101
kgp11686146 2 142745416 LRP1B G A 3.41E−05 0.21 0.026 0.116 0 2 8 24 147 95
rs11085044 19 3890641 ATCAY G A 3.52E−05 0.48 0.232 0.409 14 22 44 55 97 44
kgp3730395 9 91520540 C A 3.53E−05 0.47 0.287 0.459 14 23 61 65 80 33
rs2175121 9 108497519 TMEM38B A G 3.58E−05 3.42 0.182 0.062 5 0 46 15 103 106
kgp487328 23 26134026 G A 3.71E−05 0.31 0.071 0.162 0 2 22 40 133 79
kgp1912531 2 137850215 THSD7B A G 3.79E−05 2.64 0.247 0.099 13 3 50 18 91 100
kgp9450430 20 44085460 A G 3.80E−05 0.41 0.168 0.314 4 9 44 58 107 54
kgp2391411 2 43425645 G A 3.87E−05 0.46 0.212 0.380 8 20 49 52 96 49
rs10816302 9 108486533 TMEM38B G A 4.07E−05 3.39 0.181 0.062 5 0 46 15 104 106
rs7020402 9 108530638 TMEM38B A G 4.07E−05 3.39 0.181 0.062 5 0 46 15 104 106
rs1979993 9 108534505 TMEM38B A G 4.07E−05 3.39 0.181 0.062 5 0 46 15 104 106
rs1979992 9 108535330 TMEM38B A G 4.07E−05 3.39 0.181 0.062 5 0 46 15 104 106
rs6032209 20 44087073 A G 4.09E−05 0.42 0.175 0.325 4 11 46 36 104 53
kgp7521990 1 105666878 C A 4.38E−05 0.32 0.068 0.183 1 3 19 38 134 80
kgp2451249 1 223872873 A G 4.39E−05 3.66 0.165 0.054 3 0 45 13 107 108
kgp8796185 1 223716508 CAPN8 G A 4.39E−05 3.66 0.165 0.054 3 0 45 13 107 108
rs2241883 2 88424066 FABP1 A G 4.46E−05 0.46 0.274 0.438 9 22 67 62 79 37
rs343087 12 66260924 HMGA2 G A 4.49E−05 2.97 0.205 0.070 12 0 39 17 103 104
rs4894701 3 174931730 NAALADL2 A C 4.62E−05 2.12 0.556 0.384 44 16 81 61 27 44
kgp18525257 9 108499628 TMEM38B G A 4.63E−05 3.41 0.177 0.062 4 0 47 15 104 106
kgp18379774 9 108504407 TMEM38B G A 4.63E−05 3.41 0.177 0.062 4 0 47 15 104 106
rs10512340 9 108511163 TMEM38B G A 4.63E−05 3.41 0.177 0.062 4 0 47 15 104 106
rs10125298 9 108555594 C A 4.63E−05 3.41 0.177 0.062 4 0 47 15 104 106
kgp759150 4 40385906 G A 4.79E−05 2.19 0.552 0.388 42 13 86 68 26 40
rs10124492 9 108527455 TMEM38B T A 4.79E−05 3.36 0.180 0.062 5 0 45 15 103 106
kgp3812034 2 43427044 A G 4.88E−05 0.47 0.217 0.383 8 20 50 52 94 48
rs5024722 7 141858688 A G 4.90E−05 0.41 0.159 0.302 3 9 43 55 108 57
rs11691553 2 60303554 C A 4.92E−05 0.47 0.301 0.471 11 28 70 57 72 35
kgp11453406 10 121435955 BAG3 C A 4.96E−05 0.46 0.208 0.368 5 19 54 51 95 51
rs196341 10 121416611 BAG3 G A 5.02E−05 0.46 0.206 0.367 5 19 53 50 95 51
rs10203396 2 60305110 A G 5.26E−05 0.48 0.303 0.471 11 28 72 58 72 35
rs7579987 2 60307009 G C 5.26E−05 0.48 0.303 0.471 11 28 72 58 72 35
rs7862565 9 108592419 G A 5.29E−05 3.46 0.171 0.058 4 0 45 14 106 107
kgp11514107 2 65247253 SLC1A4 G A 5.29E−05 3.46 0.171 0.058 3 1 47 12 105 108
rs4822644 22 26134163 G A 5.29E−05 0.34 0.081 0.194 0 3 25 41 130 77
rs2136408 9 108497654 TMEM38B A C 5.39E−05 3.33 0.181 0.063 5 0 46 15 104 104
rs1545223 2 88423510 FABP1 A G 5.31E−05 0.48 0.276 0.438 9 22 67 62 78 37
rs17329014 2 60299921 G A 5.65E−05 0.46 0.206 0.364 5 18 54 52 96 51
rs2058742 17 70040547 C A 5.65E−05 2.30 0.348 0.194 17 4 74 39 64 78
kgp4420791 12 89819166 POC1B G A 5.74E−05 0.11 0.010 0.074 0 0 3 18 152 103
kgp7714238 6 145587514 G A 5.74E−05 0.11 0.010 0.074 0 0 3 18 152 103
rs13394010 2 60302746 A G 5.76E−05 0.48 0.303 0.471 11 28 72 57 72 35
kgp7924485 2 60292120 A G 5.80E−05 0.40 0.120 0.256 2 9 33 44 119 68
kgp8174785 1 110053148 G C 5.85E−05 0.45 0.245 0.401 5 19 66 59 84 43
kgp10090631 7 11754881 THSD7A A G 5.85E−05 2.11 0.500 0.331 38 10 79 58 38 50
kgp1683448 9 108449079 A G 5.95E−05 3.90 0.149 0.046 2 0 42 11 110 109
kgp8777939 6 139004920 A G 5.98E−05 2.05 0.455 0.281 33 12 75 44 47 65
rs16930057 8 63906122 G A 5.99E−05 0.40 0.123 0.256 1 8 36 46 117 67
kgp7181058 14 98385698 G A 6.10E−05 Zero 0.000 0.050 0 0 0 12 155 109
kgp11711524 9 108546438 G A 6.20E−05 3.34 0.175 0.062 4 0 46 15 104 106
kgp6505544 7 71953948 G A 6.23E−05 3.00 0.203 0.083 5 0 53 20 97 101
rs623011 17 68259446 G A 6.26E−05 2.47 0.294 0.153 9 3 73 31 73 87
kgp355027 11 115964147 A G 6.28E−05 0.37 0.101 0.223 1 4 29 46 123 71
kgp767200 5 3221345 A G 6.46E−05 2.95 0.217 0.097 2 1 62 21 88 97
kgp5908616 2 60329823 A C 6.48E−05 0.49 0.289 0.459 11 29 67 53 76 39
kgp3205849 10 121531725 INPP5P A G 6.51E−05 0.44 0.167 0.318 4 14 43 47 106 57
kgp9320791 2 60309952 C G 6.54E−05 0.48 0.305 0.471 11 28 72 58 71 35
kgp3267884 9 14639380 ZDHHC21 G A 6.61E−05 0.46 0.206 0.360 3 18 58 51 94 52
rs13002663 2 145230163 ZEB2, ZEB2 G A 6.62E−05 0.49 0.306 0.475 12 30 71 55 72 36
kgp8767692 15 66333821 MEGF11 G A 6.68E−05 0.16 0.016 0.087 0 0 5 21 150 100
kgp28532436 15 62968836 TLN2 G A 6.70E−05 19.85 0.071 0.004 0 0 22 1 133 120
rs9346979 6 164309479 G A 6.81E−05 0.49 0.303 0.471 15 26 64 62 76 33
rs714342 11 110807983 A C 6.91E−05 2.21 0.465 0.310 25 9 94 57 36 55
kgp8469954 2 135163015 MGAT5 G A 7.03E−05 0.27 0.042 0.136 0 2 13 29 142 90
kgp2709692 18 3000808 LPIN2 C A 7.22E−05 0.09 0.006 0.066 0 0 2 16 132 105
rs10510774 3 54919351 CACNA2O3 A G 7.26E−05 0.30 0.062 0.163 0 1 19 37 135 82
kgp8169636 18 29206763 B4GALT6 G A 7.44E−05 0.25 0.032 0.124 0 3 10 24 145 94
kgp3593828 5 173993252 C A 7.46E−05 2.36 0.306 0.161 12 4 71 31 72 86
kgp11010680 15 25717889 A G 7.47E−05 2.73 0.244 0.120 4 0 67 29 83 92
rs1387768 5 173993166 A G 7.54E−05 2.37 0.308 0.163 12 4 71 31 71 85
kgp11627530 14 78954642 NRKN3 A G 7.55E−05 0.28 0.039 0.136 0 4 12 25 143 92
kgp10404633 9 138136993 G A 7.60E−05 8.30 0.087 0.012 0 0 27 3 128 118
kgp8372910 9 138138723 G A 7.60E−05 8.30 0.087 0.012 0 0 27 3 128 118
kgp11206453 3 54928104 CACNA2D3 G A 7.63E−05 0.31 0.061 0.161 0 1 19 37 136 83
rs11836970 8 604262 A C 7.68E−05 2.13 0.390 0.227 23 8 74 39 57 74
kgp9795732 15 88117171 C A 7.71E−05 0.37 0.082 0.206 2 7 21 35 130 77
rs2934491 16 84905542 CRISPLD2 G A 7.81E−05 0.48 0.284 0.446 12 23 64 62 79 36
kgp9368119 7 11707419 THSD7A A G 7.87E−05 0.48 0.332 0.496 15 28 73 64 67 29
rs4709792 6 164316375 G A 7.93E−05 0.49 0.300 0.467 15 26 63 61 72 34
rs17400875 2 60295736 A C 7.94E−05 0.47 0.210 0.364 5 18 55 52 95 51
kgp10152733 9 108462735 TMEM388 G A 7.97E−05 3.17 0.181 0.066 5 0 46 16 104 105
kgp12426624 3 54926209 CACNA2O3 C A 7.99E−05 0.31 0.065 0.165 0 1 20 38 135 82
kgp55646 10 121282886 RGS10 G A 8.00E−05 0.47 0.247 0.405 11 17 54 64 89 40
kgp10922969 6 80260277 G A 8.07E−05 0.29 0.049 0.146 0 2 15 31 139 87
kgp7331172 18 66533114 CCOC102B A G 8.21E−05 2.78 0.223 0.099 6 0 57 24 92 97
kgp6666134 10 129386358 T A 8.36E−05 2.32 0.309 0.161 15 3 64 33 73 85
kgp6603796 16 84910897 CRISPLD2 G A 8.42E−05 0.48 0.260 0.421 10 21 58 60 82 40
kgp9018750 6 164312470 A G 8.44E−05 0.49 0.305 0.471 15 26 64 62 75 33
rs858341 6 132160455 ENPP1 A G 8.44E−05 2.06 0.464 0.298 33 10 26 52 44 59
kgp4096263 15 70333438 A G 8.58E−03 3.36 0.168 0.058 4 0 43 14 104 106
kgp5159037 2 65253764 A G 8.60E−05 2.85 0.208 0.083 7 1 50 18 97 101
rs423239 9 92856946 G A 8.62E−05 2.77 0.216 0.091 7 1 53 20 95 100
rs343092 12 66250940 HMGA2 C A 8.67E−05 2.87 0.197 0.070 11 0 39 17 105 104
kgp7178233 5 117621827 C A 8.81E−05 2.53 0.261 0.128 10 0 61 31 84 90
kgp3218351 11 110802128 G A 9.03E−05 2.19 0.445 0.293 24 7 90 57 41 57
kgp10544659 1 223783531 G A 9.08E−05 3.48 0.159 0.054 3 0 43 13 108 108
P1_M_061510_11_106_M 11 27308202 D 1 9.08E−05 0.48 0.290 0.450 13 22 64 65 78 34
kgp6023196 17 68271273 A C 9.22E−05 2.25 0.339 0.190 15 5 75 36 65 80
kgp4056892 20 44087774 C G 9.23E−05 0.43 0.165 0.302 3 9 45 55 107 57
rs484482 15 55418825 A G 9.31E−05 4.13 0.133 0.037 2 0 37 9 115 112
kgp6737096 15 66299395 MEGF11 G A 9.33E−05 0.18 0.019 0.091 0 0 6 22 149 99
kgp6076976 1 105663380 A T 9.53E−05 0.30 0.058 0.155 0 1 18 35 137 83
rs9597498 13 57637550 G A 9.71E−05 1.97 0.458 0.285 37 12 68 45 50 64
rs419132 6 32210799 A G 9.75E−05 2.02 0.442 0.271 32 11 72 42 50 65
kgp29794723 10 18397332 A G 9.75E−05 0.14 0.013 0.079 0 0 4 19 150 102
kgp6091119 17 44879640 WNT3 A G 9.98E−05 0.21 0.023 0.103 0 1 7 21 148 98
kgp10351364 8 103604706 G A 1.00E−04 2.09 0.538 0.373 40 13 77 62 29 43
rs9326361 6 139006406 A G 1.00E−04 1.99 0.468 0.298 34 14 76 44 44 63
kgp3991733 1 105671167 T A 1.01E−04 0.34 0.071 0.179 1 3 20 37 134 80
rs6687976 1 105674536 C A 1.01E−04 0.34 0.071 0.179 1 3 20 37 134 80
2-Priority Genes rs6110157 20 14055947 MACROD2 A G 1.82E−04 0.47 0.193 0.335 6 13 47 55 100 53
(extreme)
2-Priority Genes kgp4011779 10 100454360 HPSE2 G A 2.53E−04 0.13 0.010 0.066 0 0 3 16 151 105
(extreme)
0-Priority-Model rs16886004 7 78021500 MAG12 A G 6.08E−04 2.48 0.197 0.092 4 2 55 18 98 100
2-Priority Genes kgp3496814 13 31336379 ALOX5AP C A 6.09E−04 0.55 0.416 0.566 28 39 73 59 54 23
(extreme)
0-Priority-Model, rs10162089 13 31316738 ALOX5AP G A 9.40E−04 1.78 0.503 0.357 43 14 69 57 42 48
Priority Gene
2-Priority Genes rs3885907 13 31314455 ALOX5AP A C 9.70E−04 1.77 0.484 0.319 41 13 68 36 44 52
(extreme)
0-Priority-Model rs1694408 6 32786833 C G 1.15E−03 1.86 0.408 0.277 22 10 81 47 50 64
0-Priority-Model kgp8817856 6 32744440 G A 1.17E−03 0.54 0.369 0.500 17 26 79 69 57 26
2-Priority Genes rs17238927 13 31332391 AUOX5AP G A 1.25E−03 0.07 0.003 0.042 0 0 1 10 154 110
(extreme)
2-Priority Genes rs9671124 13 31324253 ALOX5AP G A 1.26E−03 1.74 0.523 0.380 46 17 70 58 39 46
(extreme)
2-Priority Genes rs4769060 13 31337477 ALOX5AP A G 1.27E−03 1.77 0.481 0.343 38 12 73 59 44 50
(extreme)
0-Priority-Model kgp24415534 2 174156875 G A 1.32E−03 0.07 0.003 0.041 0 0 1 10 154 111
2-Priority Genes rs4075692 13 31323342 ALOX5AP G A 1.55E−03 1.72 0.519 0.380 45 17 71 58 39 46
(extreme)
2-Priority Genes rs11147439 13 31325643 ALOX5AP C A 1.86E−03 0.59 0.397 0.533 28 33 67 63 60 25
(extreme)
2-Priority Genes kgp3276689 10 100396003 HPSE2 C A 1.97E−03 2.16 0.205 0.104 9 0 45 25 100 95
(extreme)
2-Priority Genes kgp304921 20 14017077 MACROD2 A G 2.05E−03 0.31 0.030 0.097 1 2 7 19 144 98
(extreme)
2-Priority Genes rs3803277 13 31318308 ALOX5AP C A 2.06E−03 0.59 0.406 0.541 28 35 70 61 57 25
(extreme)
2-Priority Genes kgp5440506 13 31320543 ALOX5AP G A 2.49E−03 0.60 0.399 0.533 29 33 65 62 60 25
(extreme)
2-Priority Genes rs9671182 13 31321138 ALOX5AP C G 2.75E−03 0.60 0.406 0.538 29 33 68 63 58 24
(extreme)
0-Priority-Model kgp8110667 22 32716792 G A 2.78E−03 Infinity 0.035 0.000 0 0 11 0 144 121
2-Priority Genes rs4254166 13 31322949 ALOX5AP A G 2.87E−03 0.60 0.403 0.533 28 33 69 63 58 25
(extreme)
2-Priority Genes rs4356336 13 31319546 ALOX5AP A G 2.90E−03 0.60 0.406 0.532 29 34 68 62 58 25
(extreme)
2-Priority Genes rs11003051 10 78921392 KCNMA1 G A 3.11E−03 0.39 0.055 0.124 0 1 17 28 138 92
(extreme)
2-Priority Genes rs10278591 7 1921362 MADIL1 G A 3.15E−03 1.88 0.281 0.174 13 2 61 18 81 81
(extreme)
2-Priority Genes rs4360791 13 31318030 ALOX5AP G A 3.39E−03 0.61 0.416 0.545 30 36 69 60 56 25
(extreme)
2-Priority Genes kgp2715873 13 31320249 ALOX5AP G A 3.78E−03 0.61 0.406 0.533 29 33 68 63 58 25
(extreme)
2-Priority Genes rs9670531 13 31321069 ALOX5AP A G 3.78E−03 0.61 0.406 0.533 29 33 68 63 58 25
(extreme)
2-Priority Genes rs9385047 13 31321289 ALOX5AP A T 3.78E−03 0.61 0.406 0.533 29 33 68 63 58 25
(extreme)
2-Priority Genes rs4584668 13 31319553 ALOX5AP A T 3.85E−03 0.61 0.406 0.533 29 33 68 62 58 25
(extreme)
2-Priority Genes rs9508832 13 31314264 ALOX5AP G A 4.31E−03 1.65 0.445 0.322 35 11 68 56 52 54
(extreme)
1-Priority Variant rs2487896 10 100802380 HPSE2 G A 4.38E−03 0.51 0.113 0.204 3 6 29 37 123 77
(extreme)
1-Priority Genes kgp7117398 7 1915282 MADIL1 C A 4.55E−03 1.83 0.261 0.178 13 2 61 39 81 80
(extreme)
1-Priority Variant rs10988087 9 131443671 A G 5.08E−03 0.33 0.029 0.083 0 1 9 18 146 101
(extreme)
0-Priority-Model kgp6599438 20 40843626 PTPRT G A 5.13E−03 0.22 0.013 0.054 0 0 4 13 151 108
0-Priority-Model, rs3135391 6 32410987 HLA-DRA G A 6.38E−03 0.57 0.190 0.289 6 9 47 52 102 60
Priority Variant
1-Priority Variant rs1573206 20 40921149 PTPRT G A 7.11E−03 0.55 0.139 0.227 2 7 39 41 114 73
(extreme)
2-Priority Genes kgp4370912 10 78918297 KCNMA1 C A 7.39E−03 0.42 0.005 0.117 0 1 17 26 138 93
(extreme)
1-Priority Variant rs3135388 6 32413051 G A 7.54E−03 0.58 0.190 0.288 6 9 47 51 102 60
(extreme)
0-Priority-Model kgp7747883 18 74804250 MBP G A 9.26E−03 0.63 0.321 0.430 16 22 67 60 71 39
1-Priority Variant rs6097801 20 52767434 G A 4.35E−02 0.63 0.110 0.174 7 3 20 36 128 82
(extreme)
(Note: Odds Ratio >1 = Minor Allele is associated with Response. Odds Ratio <1 = Minor Allele Associated with Non-Response)
TABLE 30
Placebo SNPs
PLACERO COHORT
Major Minor P-value Odds Ratio Minor Allele Minor Allele DD DD (Non- Dd Dd (Non- dd dd (non-
Chromo- Allele Allele (Armitage (Minor Freq. Freq. (Non- (Re- Re- (Re- Re- (Re- Re-
Name some Position Gene(s) (d) (D) Test) Allele) (Responders) Responders) sponders) sponders) sponders) sponders) sponders) sponders)
kgp433351 8 41496314 A G 2.69E−06 0.339857466 0.231578947 0.46039604 6 19 32 55 57 27
kgp2877462 6 1644677 GMDS G A 2.73E−06 9.628676471 0.142105263 0.01980198 0 0 27 4 68 97
kgp2920925 17 39694480 G A 9.45E−06 0.270712068 0.1 0.272277228 0 6 19 43 76 52
rs209568 8 17612639 MTUS1 A G 1.13E−05 3.636556912 0.273684211 0.108910891 4 0 44 22 47 79
kgp7653470 17 39694186 A G 1.14E−05 0.269888943 0.1 0.267326733 0 5 19 44 76 52
rs7119480 11 84347636 DLG2 G A 1.31E−05 0.313880826 0.142105263 0.526732673 1 9 25 48 69 44
kgp10148554 4 89767803 FAM13A A G 1.54E−05 6.801291939 0.154255319 0.024752475 3 0 23 5 68 96
kgp11285883 9 2953403 C A 1.57E−05 2.463948851 0.457894737 0.232673267 26 5 35 37 34 59
kgp6042557 3 194640716 LOC109507391 A G 1.64E−05 0.074707387 0.010526316 0.12 0 1 2 21 93 77
kgp10969246 4 89761443 FAM13A A G 1.74E−05 6.733466513 0.154255319 0.025 3 0 23 5 68 95
kgp11604017 11 118074117 AMICA1 G A 1.74E−05 2.890031976 0.376344086 0.183168317 11 3 48 31 34 67
rs3856038 9 2988280 C A 1.75E−05 2.390793359 0.526315789 0.297029303 33 7 34 46 28 48
rs7698655 4 89756076 FAM13A G A 1.79E−05 6.706712195 0.152631579 0.024752475 3 0 23 5 69 96
kgp9509440 4 89759159 FAM13A G A 1.79E−05 6.706712195 0.152631579 0.024752475 3 0 23 5 69 96
kgp6889327 4 89766553 FAM13A A G 1.79E−05 6.706712195 0.152631579 0.024752475 3 0 23 5 69 96
rs7696391 4 89789287 FAM13A A C 1.79E−05 6.706712195 0.152631579 0.024752475 3 0 23 5 69 96
rs11947777 4 89768744 FAM13A A G 2.02E−05 6.639861024 0.152631579 0.025 3 0 25 5 69 95
kgp6301155 4 89766647 FAM13A A C 2.29E−05 6.573008284 0.152631579 0.025252525 3 0 23 5 69 94
rs12472695 2 65804266 G A 2.31E−05 0.381410892 0.310526316 0.314851485 10 21 39 62 46 18
rs4978567 9 116880005 G A 2.50E−05 0.400621674 0.321052632 0.535353535 10 37 41 52 44 20
rs17419416 6 15863865 A G 2.51E−05 0.2975848 0.105263158 0.272377238 0 7 20 41 75 53
kgp7778343 9 2965090 A G 2.56E−05 2.42370702 0.489361702 0.27 27 6 38 42 29 52
rs2618065 11 75991931 G A 2.73E−05 0.343008454 0.194736842 0.376237624 2 10 33 56 60 35
kgp3188 2 65804244 A G 2.99E−05 0.38808492 0.356382979 0.559405941 13 25 41 63 40 13
rs9948420 18 13358206 C18orf7 G A 3.14E−05 2.776643091 0.404255319 0.217821782 12 3 52 38 30 60
kgp5747456 2 23932556 G A 3.24E−05 2.04E+16 0.078947368 0 0 0 15 0 80 101
kgp6429231 15 62931802 MGC15885 G A 3.24E−05 2.04E+16 0.078947368 0 0 0 15 0 80 101
kgp10215554 16 8753573 A G 3.30E−05 4.029736689 0.205263158 0.064356436 3 0 33 13 59 88
rs7123506 11 84218362 DLG2 G A 3.35E−05 0.312509142 0.121052632 0.287126713 0 7 23 44 72 50
rs1715441 11 118072181 AMICA1 G A 3.37E−05 2.763225218 0.368421053 0.183168317 11 3 48 31 36 67
rs1793174 11 114074337 AMICA1 G A 3.37E−05 2.763235218 0.368421053 0.183168317 11 3 48 31 36 67
rs11562998 2 51814215 A G 3.41E−05 6.516129255 0.142105263 0.024752475 2 0 23 5 70 96
rs11563025 2 51864372 A G 3.41E−05 6.516129255 0.142105263 0.024752475 2 0 23 5 70 96
kgp9909702 8 112742367 A C 3.46E−05 0.411700671 0.378947368 0.589108911 14 33 48 53 37 15
kgp541892 5 73992881 HEXB A G 3.56E−05 0.287914141 0.089473684 0.247524752 3 3 11 44 81 54
rs961090 15 40617414 A G 3.56E−05 2.930247466 0.305263158 0.128712871 9 2 40 22 46 77
kgp3697615 12 92450247 LOC256021 C G 3.67E−05 2.591824755 0.445054945 0.245 16 6 49 37 26 57
rs16846161 2 212297838 ER884 A G 3.72E−05 12.04169614 0.117021277 0.01010101 2 0 18 2 74 97
kgp6828277 9 8373943 PTPRD A C 3.76E−05 3.336857878 0.260638298 0.103960396 3 2 43 17 48 82
rs2662 17 39670098 KRTIS C A 3.79E−05 0.296809986 0.105263158 0.262376238 0 5 20 43 75 53
rs7949751 11 118072373 AMICA1 A G 3.80E−05 2.71195824 0.378947368 0.193069307 11 4 50 31 34 66
rs1393040 9 2985743 G A 3.82E−05 2.338232703 0.484042533 0.267326733 28 6 35 42 31 53
kgp22839559 A C 3.97E−05 2.824453621 0.340425532 0.16 10 2 44 28 40 70
rs3894712 5 73973851 C A 3.98E−05 0.299943516 0.089473684 0.252475248 3 5 11 41 81 55
kgp9143704 17 14355591 G A 4.08E−05 2.349680919 0.589473684 0.378237624 33 15 46 46 16 40
kgp5949515 5 62708211 G A 4.12E−05 0.37608267 0.236842105 0.425742574 3 16 39 54 53 31
rs10038844 5 62709953 A G 4.12E−05 0.37608267 0.236842105 0.425742574 3 16 39 54 53 31
kgp12562255 1 201348672 G A 4.21E−05 21.79487179 0.089473684 0.004950495 0 0 17 1 78 100
kgp4575797 11 118083664 AMICA1 G A 4.25E−05 2.730419244 0.362421053 0.185 11 3 48 31 36 66
rs4647183 4 171919792 G A 4.28E−05 2.800107938 0.336842105 0.158415842 10 2 44 28 41 71
kgp5326762 4 171939426 G A 4.28E−05 2.800107938 0.336842105 0.158415842 10 2 44 28 41 71
rs6811337 4 171939724 G A 4.28E−05 2.800107938 0.336842105 0.158415842 10 2 44 28 41 71
rs7680970 4 89772301 FAMI3A C A 4.40E−05 5.589687003 0.152631579 0.02970297 3 0 23 6 69 95
kgp7006201 20 55128573 G A 4.42E−05 9.27027027 0.110526316 0.014851485 0 0 21 3 74 98
rs4797764 18 13382265 C18orf1 A C 4.48E−05 2.492352353 0.521276596 0.521782178 22 10 54 45 18 46
kgp6990559 1 7014101 CAMTA1 G A 4.49E−05 0.44328707 0.35106383 0.577319588 15 35 36 42 43 20
kgp4970670 8 17626306 MTUS1 G A 4.50E−05 3.327473192 0.252631579 0.099009901 4 1 40 18 51 82
rs1424226 6 122363499 A G 4.68E−05 0.404824911 0.3 0.5 9 22 39 57 47 22
kgp5894351 16 76018855 C A 4.73E−05 2.627713518 0.457894737 0.27 14 7 59 40 22 53
kgp4892427 9 2995617 G A 4.74E−05 2.303512108 0.515789474 0.301980198 31 7 36 47 28 47
rs11750747 5 73973283 A G 4.86E−05 0.299314836 0.089473884 0.247524752 3 4 11 42 81 55
rs12233980 5 73975094 G A 4.86E−05 0.299314836 0.089473884 0.247524752 3 4 11 42 81 55
kgp3624014 16 6442184 RBFOX1 G A 4.92E−05 2.364225084 0.573684211 0.366336634 10 14 49 46 16 41
kgp3598966 4 7649861 SORC52 G A 4.94E−05 0.324801511 0.110526316 0.377227723 1 8 19 40 75 53
kgp10762962 15 34983455 G A 5.10E−05 4.525507056 0.173684211 0.044554455 3 0 27 9 65 92
rs3847233 9 2987835 G A 5.11E−05 2.294890779 0.516129032 0.3 31 7 34 46 28 47
rs7819949 8 41387921 GIN54 G A 5.23E−05 0.376526131 0.242105263 0.425742574 6 12 34 62 55 27
kgp4985243 7 136556162 CHRM2 G A 5.24E−05 3.777144291 0.210626316 0.074257426 2 0 36 15 57 86
rs6577395 1 6991925 CAMTA1 A G 5.34E−05 0.451723956 0.367021272 0.589108911 16 38 37 43 41 20
kgp4037661 16 76019450 C A 5.36E−05 2.607793598 0.457446809 0.27 14 2 58 40 22 53
rs17187123 4 171969779 LOC100506122 G A 5.39E−05 2.760718495 0.335106383 0.158415842 10 2 43 28 41 71
rs9953274 18 13317297 C18orf1 G A 5.43E−05 2.632532227 0.415789474 0.232673267 14 3 51 41 30 57
rs7846783 9 2958182 A G 5.46E−05 2.308218163 0.452631579 0.242574257 25 6 36 37 34 58
rs3858035 9 2968044 A C 5.50E−05 2.297809929 0.484042553 0.272277228 27 7 37 41 30 53
kgp1682126 5 2047397 G A 5.53E−05 0.048188869 0.005263158 0.099009901 0 1 1 18 94 82
rs17245674 4 171884710 G A 5.64E−05 2.786056066 0.331578947 0.158415842 9 2 45 28 48 71
rs967616 4 171888232 A G 5.64E−05 2.786056066 0.331578947 0.158415842 9 2 45 28 41 71
kgp4456934 2 218174378 DIRC3 G A 5.64E−05 3.792998699 0.205163158 0.065 4 0 31 13 60 87
rs12881439 14 37105853 A G 5.87E−05 0.337727502 0.142105263 0.306930693 0 8 27 46 68 47
kgp5927782 14 37108518 A G 5.87E−05 0.357727502 0.142105263 0.306930693 0 8 27 46 68 47
rs8000689 13 41043438 TTL G A 6.00E−05 0.446273903 0.384210626 0.599009901 14 40 45 41 36 20
kgp8145845 6 15873989 A C 6.04E−05 0.348762475 0.189473684 0.356435644 0 9 35 54 59 38
rs10495115 1 219089109 C A 6.04E−05 2.896745105 0.3 0.133683366 7 2 43 23 45 76
rs3858034 9 2964750 A G 6.07E−05 2.302490296 0.478947368 0.27 27 6 37 42 31 52
kgp4137144 1 219091068 A G 6.13E−05 6.188590011 0.134297872 0.025 2 0 23 5 70 95
kgp7932108 9 110434545 A G 6.28E−05 3.182096036 0.25 0.094059406 6 1 35 17 53 83
kgp8847137 11 118078958 AMICA1 A G 6.37E−05 2.65389832 0.365591398 0.185 11 3 46 31 36 66
rs1393037 9 2968451 A G 6.42E−05 2.286704865 0.484042553 0.272727273 27 7 37 40 30 52
rs1508515 4 178932189 C G 6.80E−05 2.721514946 0.333333333 0.158425842 10 2 42 38 41 71
rs7681006 4 18140181 G A 6.80E−05 2.292936797 0.552631579 0.346534653 30 12 45 46 20 43
kgp4591145 3 112807116 A G 7.17E−05 0.414208739 0.394736842 0.589108911 13 32 49 55 33 14
rs3768769 2 113764983 IL36A A G 7.21E−05 4.303214495 0.173684211 0.04950495 2 0 29 10 64 91
kgp3488270 1 20335423 G C 7.30E−05 0.266656346 0.063257895 0.205 1 4 10 33 84 63
rs2354380 2 51826155 A C 7.48E−05 5.489851381 0.143617021 0.02970297 2 0 23 6 69 95
rs13168893 5 62732760 A C 7.49E−05 0.390251325 0.268421053 0.45049505 4 17 43 57 48 27
kgp6213972 3 194426284 G A 7.52E−05 0.216311903 0.042105263 0.168316832 0 3 8 28 87 70
rs1357718 5 105355890 A G 7.71E−05 4.070798901 0.186170213 0.060606061 1 0 33 12 60 87
kgp5924341 6 23943424 G A 7.71E−05 0.161887188 0.026313789 0.135 0 1 5 25 90 74
rs6459418 6 15860342 A C 7.78E−05 0.353819225 0.191489362 0.356435644 0 9 36 54 58 38
rs1905248 12 52007003 SCN8A G A 7.84E−05 2.853251243 0.310526316 0.148514851 6 2 47 26 42 73
kgp7151153 3 79590648 ROBO1 G A 7.86E−05 1.980515837 0.184210526 0.04950495 4 1 27 8 64 92
rs3858036 9 2968107 A G 7.92E−05 2.248089873 0.478947368 0.272277228 27 7 37 41 31 53
kgp10836214 9 2969061 A C 7.92E−05 2.248089873 0.478947368 0.272277228 27 7 37 41 31 53
kgp625941 5 73973306 G A 7.95E−05 0.3102772 0.089473684 0.242574257 3 4 11 41 81 56
kgp2176915 5 36732366 C A 8.12E−05 20.25316456 0.084210526 0.004950495 0 0 16 1 79 100
rs4740708 9 2993975 G A 8.20E−05 2.230445246 0.510638298 0.301980198 31 7 34 47 29 47
kgp1432800 9 111389847 A C 8.22E−05 4.705307757 0.157894737 0.03960396 2 0 26 8 67 93
rs7231366 18 13332691 C18orf1 A G 8.23E−05 2.523393135 0.421052632 0.237373737 14 5 52 37 29 57
rs28993969 2 113762224 A G 8.31E−05 3.673422044 0.2 0.064356436 4 0 30 13 61 88
kpg3420309 4 15213767 A G 8.60E−05 5.414105514 0.142105263 0.02970297 2 0 23 6 70 95
kgp3287349 4 15224995 A G 8.60E−05 5.414105514 0.142105263 0.02920297 2 0 23 6 70 95
rs12043743 1 196502836 XCNT2 T A 8.61E−05 0.160256411 0.026315789 0.128712871 0 0 5 26 90 75
kgp394638 10 112163082 G A 8.68E−05 3.443845133 0.215789474 0.070707071 6 0 29 14 60 85
kgp24521552 2 144072847 ARHGAP15 C A 8.86E−05 4.219905015 0.173684211 0.045 4 0 25 9 66 91
rs263247 8 131792219 A G 8.87E−05 0.379472909 0.175531915 0.351485149 3 11 27 49 64 41
kgp2993366 6 6726140 C A 8.88E−05 2.392490753 0.538043478 0.340206186 25 10 49 46 18 41
kgp11755256 2 42245135 G A 9.99E−05 0.379232018 0.143617021 0.321782178 1 14 25 37 68 50
rs8018807 14 27905391 A G 9.00E−05 0.445075158 0.319148936 0.524752475 10 30 40 46 44 25
rs7961005 12 75849425 A G 9.11E−05 0.325552876 0.105263158 0.26 0 7 20 38 75 55
kgp1211163 11 98961805 CNTN5 C A 9.12E−05 5.531933083 0.136842105 0.02970297 1 0 24 6 70 95
rs528065 2 23859449 KLHL29 G A 9.24E−05 2.448976995 0.442105263 0.257425743 19 3 46 46 30 32
rs13386874 2 51820543 A G 9.25E−05 2.638975938 0.321052632 0.148514851 12 1 37 28 46 72
kgp1758575 12 14433784 A G 9.25E−05 2.322238139 0.457894737 0.262376238 18 10 51 33 26 58
kgp6081880 4 171852630 G A 9.39E−05 2.692096282 0.326315789 0.158415842 9 2 44 28 42 71
kgp956070 2 205936350 PARD3B G A 9.39E−05 0.371996312 0.142105263 0.315 2 11 23 41 70 48
rs35615951 2 133778855 NCKAP5 G A 9.41E−05 2.317383014 0.478723404 0.282178218 23 8 46 41 26 52
kgp8644305 18 74021780 G A 9.50E−05 8.396863212 0.110526316 0.014851485 1 0 19 3 75 98
P1 M 061510 18 31319566 t D 9.51E−05 0.229965157 0.054347826 0.173267327 0 0 10 35 82 66
18 342 P
kgp12253568 3 79428265 ROBO1 G A 9.55E−05 4.28904266 0.168421053 0.03960396 4 1 24 6 67 94
rs1397481 2 205894489 PARD3B G A 9.56E−05 0.368096506 0.142105263 0.311881188 2 10 23 43 20 48
rs1026894 12 52019159 SCN8A A G 9.57E−05 2.756153394 0.326315789 0.163366337 7 2 48 29 40 70
kgp7161038 2 53521025 A G 9.70E−05 0.088043478 0.010638298 0.099009901 0 0 2 20 92 81
rs1534647 2 62038088 G A 9.72E−05 3.3378955 0.221052632 0.079207921 5 0 32 16 58 85
kgp5252824 4 123558223 A G 9.87E−05 0.051605754 0.005263158 0.094059406 0 1 1 17 94 83
kgp5691690 5 135207935 SLC25A48 G A 9.87E−05 0.051605754 0.005263158 0.094059406 0 1 1 17 94 83
rs12341716 9 22947192 A G 9.91E−05 0.339667103 0.126313789 0.282178218 1 6 22 45 72 50
kgp6194428 6 15873854 A G 0.000100412 0.361610208 0.189473684 0.351485149 0 9 36 53 59 39
rs1883448 6 15877727 A G 0.000100412 0.361610208 0.189473684 0.351485149 0 9 36 53 59 39
(Note: Odds Ratio >1 = Minor Allele is associated with Response, Odds Ratio <1 = Minor Allele Associated with Non-Response)
TABLE 31
Predictive Model SNPs
STANDARD PHENOTYPE Gals cohort Forte cohort
Major Minor P-value Odds Ratio Minor Allele Allele Freq. P-value Odds Ratio Minor Allele Allele Freq.
Prioritized Allele Allele (Armitage (Minor Freq. (Non- (Armitage (Minor Freq. (Non-
Variants Name Chromosome Position Gene(s) (d) (D) Test) Allele) (Responders) Responders) Test) Allele) (Responders) Responders)
0-Priority genes, rs1894408 6 32786833 C G 3.02E−03 1.72 0.419 0.305 9.30E−03 1.82 0.407 0.279
Predictive Model
0-Priority genes, kgp6599438 20 40843626 PTPRT G A 3.70E−03 0.21 0.010 0.046 1.55E−02 0.28 0.018 0.057
Predictive Model
0-Priority genes, kgp7747813 18 74804250 MBP G A 3.55E−02 0.70 0.346 0.429 9.82E−03 0.57 0.325 0.451
Predictive Model
0-Priority genes, rs10162089 13 31316738 ALOX5AP G A 7.79E−03 1.56 0.508 0.398 3.16E−02 1.58 0.457 0.344
Predictive Model
0-Priority in kgp24415534 2 174156375 G A 3.40E−05 0.05 0.003 0.050 1.10E−02 0.14 0.005 0.033
Predictive Model
0-Priority in rs16886004 7 78021500 MAGt2 A G 2.28E−03 2.15 0.199 0.110 3.25E−05 5.56 0.199 0.049
Predictive Model
0-Priority in kgp8817856 6 32744440 G A 6.02E−04 0.53 0.364 0.492 3.73E−04 0.46 0.419 0.598
Predictive Model
0-Priority in kgp6214351 11 75546691 UVRAG A G 3.98E−03 0.42 0.051 0.113 2.65E−04 0.26 0.043 0.131
Predictive Model
0-Priority in kgp8110667 22 32716792 G A 5.97E−03 Infinity 0.030 0.000 1.46E−02 Infinity 0.050 0.000
Predictive Model
0-Priority in rs759458 2 65245365 SLC1A4 G A 1.08E−03 1.90 0.303 0.163 4.74E−01 1.18 0.288 0.254
Predictive Model
0-Priority rs3135391 6 32410987 HLA-DRA G A 3.99E−02 0.66 0.174 0.242 4.99E−02 0.64 0.231 0.320
varients,
Predictive Model
Combined
STANDARD PHENOTYPE Odds
Major Minor P-value Ratio Minor Allele Allele Freq. DD DD (Non- Dd Dd dd dd
Prioritized Chromo- Allele Allele (Armitage (Minor Freq. (Non- (Re- re- (Re- (Non- (Re- (Non-
Variants Name some Position Gene(s) (d) (D) Test) Allele) (Responders) Responders) sponders) sponders) sponders) responders) sponders) responders)
0-Priority rs1894408 6 32286833 C G 9.82E−05 1.73 0.413 0.296 58 16 211 74 127 89
genes,
Predictive
Model
0-Priority kgp6599438 20 40843626 PTPRT G A 2.48E−04 0.26 0.014 0.050 0 0 11 18 386 163
genes,
Predictive
Model
0-Priority kgp7747883 18 74804250 MBP G A 8.64E−04 0.64 0.335 0.436 43 33 181 92 174 56
genes,
Predictive
Model
0-Priority in rs10162089 13 31316738 ALOX5AP G A 1.40E−03 1.51 0.482 0.380 96 24 190 88 110 67
Predictive
Model
0-Priority in kgp24415534 2 174156875 G A 3.98E−07 0.08 0.004 0.044 0 0 3 16 396 163
Predictive
Model
0-Priority in rs16886004 7 78021500 MAGt2 A G 9.81E−07 2.79 0.199 0.059 6 2 147 28 246 149
Predictive
Model
0-Priority in kgp8817856 6 32744440 G A 5.35E−06 0.53 0.392 0.518 50 44 208 103 135 34
Predictive
Model
0-Priority in kgp6214351 11 75546691 UVRAG A G 5.51E−06 0.35 0.046 0.119 0 2 37 39 361 140
Predictive
Model
0-Priority in kgp8110667 22 32716792 G A 1.44E−04 Infinity 0.040 0.000 1 0 30 0 367 181
Predictive
Model
0-Priority in rs759458 2 65245565 SLC1A4 G A 2.01E−03 1.39 0.295 0.207 38 7 159 61 201 113
Predictive
Model
0-Priority rs3135391 6 32410987 HLA-DRA G A 1.44E−02 0.70 0.203 0.268 20 10 172 77 257 94
varients,
Predictive
Model
(Note: Odds Ratio >1 = Minor Allele is associated with Response, Odds Ratio <1 = Minor Allele Associated with Non-Response)
Example 16 Selection of Genetic Markers for Predictive Models A total of 11 genetic variants were selected for inclusion in a preliminary multi-marker risk prediction model. Importantly, many of the identified genes have been previously implicated in MS and/or glatiramer acetate response (i.e., MAGI2, HLA-DOB/TAP2 region, MBP, ALOX5AP, and the HLA-DRB1-15:01 polymorphism).
Variants were identified and selected using a multi-step approach, beginning with the selection of replicated variants from a priority list of 35 candidate variants. This led to one variant selected for inclusion into the model: rs3135391, a marker of HLA-DPB1*1501, P<0.05 in Gala, P<0.05 in Forte, P=0.014 combined, odds ratio 1.6).
This was followed by selection of three replicated variants from a list of 4,012 variants in 30 priority genes (kgp8817856 in HLA-DQB2/DOB, p<0.001 in Gala, p<0.001 in Forte, p-value 5.33E-06, odds ratio 0.53; rs1894408 in HLA-DOB/TAP2, p<0.01 in Gala, p<0.01 in Forte, p-value 0.000098, odds ratio 1.7; and kgp7747883 in MBP, p<0.05 in Gala, p<0.01 in Forte, p-value 0.00086, odds ratio 0.64).
This was followed by a selection of two variants from a list of 25,000 candidate variants in 180 second priority genes (kgp6599438 in PTPRT, p<0.01 in Gala, p<0.05 in Forte, p-value 0.00025, odds ratio 0.26; and rs10162089 in ALOX5AP, p<0.01 in Gala, p<0.05 in Forte, p-value 0.0014, odds ratio 1.5).
Finally, three variants were selected from the entire genome-wide panel (rs16886004 in MAGI2, p<0.005 in Gala, p<0.00005 in Forte, p-value 0.00000098 combined, odds ratio 2.8; kgp24415534 in the ZAK/CDCA7 gene region, p<0.00005 in Gala, p<0.05 in Forte, p-value 0.000000398, odds ratio 0.08; and kgp8110667 in the RFPL3/SLC5A4 region, p<0.01 in Gala, p<0.05 in Forte, p-value 0.00014, odds ratio: infinity).
In addition, two variants were selected from the entire genome-wide panel using an extreme phenotype definition (kgp6214351 in the UVRAG gene, combined p-value 0.0000055, odds ratio 0.35; and rs759458 in SLC1A4, combined p-value 0.002; odds ratio 1.6). The statistics of the selected 11 SNPs are shown for the additive and allelic genetic models. The statistics of the selected 11 SNPs are shown for the additive and allelic genetic models (Tables 32 and 33, respectively).
TABLE 32
Additive Model Characteristics of Individual SNPs in Model
Additive Model
GALA cohort
Al-
Armi- Odds Al- lele
tage Ratio lele Freq.
Posi- Muta- Loca- P- (Regres- Freq. (Non-
Gene(s) Name Chr tion tion tions Source value sion) (Resp.) Resp.)
ZAK/ kgp24415534 2 174156875 non-coding — GWAS, 3.40E−05 0.05 0% 5%
CDCA7 Additive
UVRAG kgp6214351 11 75546691 non-coding INTRON GWAS, 0.003983 0.42 5% 11%
Additive,
Extreme
PTPKT kgp6599438 20 40843626 non-coding INTRON Candidate 0.003702 0.21 2% 3%
Genes (180)
MBP kgp7747883 18 74804250 non-coding INTRON Candidate 0.035519 0.70 35% 43%
Genes (30)
RFPL3/ kgp8110667 22 32716792 non-coding — GWAS, 0.005975 Inf. 3% 0%
SLCSA4 Additive
region
HLA-DQ82/ kgp8817856 6 32744440 non-coding — Candidate 0.000602 0.53 38% 49%
DO8 genes
(30) +
GWAS
ALOX5AP rs10162089 13 31316738 non-coding INTRON Candidate 0.007794 1.56 51% 40%
Genes (180)
MAGI2 rs16886004 7 78021500 non-coding INTRON GWAS, 0.002281 2.15 20% 11%
Additive
HLA-DO8/ rs1894408 6 32786833 non-coding — Candidate 0.003022 1.72 42% 31%
TAP2 Genes (30)
HLA-DRA/ rs3135391 6 32410987 Synon EXON Candidate 0.03985 0.66 17% 24%
DRB1*1501 T118T variants
SLC1A4 rs759458 2 65245365 Nonsynon EXON GWAS, 0.001079 1.90 30% 18%
V101I Additive,
Extreme
Additive Model
Forte cohort Combined cohort
Al- Al-
Armi- Odds Al- lele Armi- Odds Al- lele
tage Ratio lele Freq. tage Ratio lele Freq.
P- (Regres- Freq. (Non- P- (Regres- Freq. (Non-
Gene(s) value sion) (Resp.) Resp.) value sion) (Resp.) Resp.)
ZAK/ 0.010967 0.14 0% 3% 3.98E−07 0.06 0% 4%
CDCA7
UVRAG 0.000265 0.25 4% 13% 5.51E−06 0.35 5% 12%
PTPKT 0.015514 0.28 4% 6% 0.000248 0.26 1% 5%
MBP 0.00982 0.57 33% 45% 0.000864 0.64 34% 44%
RFPL3/ 0.014628 Inf. 5% 0% 0.000144 Inf. 4% 0%
SLCSA4
region
HLA-DQ82/ 0.000373 0.46 42% 60% 5.33E−06 0.53 39% 53%
DO8
ALOX5AP 0.031551 1.58 48% 34% 0.001396 1.51 48% 38%
MAGI2 3.25E−05 5.56 20% 5% 9.81E−07 2.79 20% 9%
HLA-DO8/ 0.0093 1.82 41% 28% 9.82E−05 1.73 41% 30%
TAP2
HLA-DRA/ 0.049871 0.64 23% 32% 0.014366 0.70 20% 27%
DRB1*1501
SLC1A4 0.47426 1.18 29% 25% 0.002005 1.59 30% 21%
Additive Model
DD Dd dd
DD (Non- Dd (Non- dd (Non-
Gene(s) (Resp.) Resp.) (Resp.) Resp.) (Resp.) Resp.)
ZAK/ 0 0 3 16 396 165
CDCA7
UVRAG 0 2 37 39 361 140
PTPKT 0 0 11 18 386 163
MBP 43 33 181 92 174 56
RFPL3/ 1 0 30 0 367 181
SLCSA4
region
HLA-DQ82/ 50 44 208 103 135 34
DO8
ALOX5AP 96 24 190 88 110 67
MAGI2 6 2 147 28 246 249
HLA-DO8/ 58 16 211 74 127 89
TAP2
HLA-DRA/ 20 10 122 77 257 94
DRB1*1501
SLC1A4 38 7 159 61 201 113
Additive Model, Extreme Phenotype
GALA cohort
Al-
Armit- Odds Al- lele
age Ratio lele Freq.
Posi- Muta- Loca- P- (Regres- Freq. (Non-
Gene(s) Name Chr tion tion tions Source value sion) (Resp.) Resp.)
ZAK/ kgp24415534 2 174156875 non-coding — GWAS, 4.38E−02 0.15 1% 5%
CDCA7 Additive
UVRAG kgp6214351 11 75546691 non-coding INTRON GWAS, 0.002442 0.20 3% 13%
Additive,
Extreme
PTPKT kgp6599438 20 40843626 non-coding INTRON Candidate 0.006737 0.00 0% 5%
Genes (180)
MBP kgp7747883 18 74804250 non-coding INTRON Candidate 0.243651 0.75 38% 43%
Genes (30)
RFPL3/ kgp8110667 22 32716792 non-coding — GWAS, 0.009445 Inf. 4% 0%
SLCSA4 Additive
region
HLA-DQ82/ kgp8817856 6 32744440 non-coding — Candidate 0.036059 0.58 37% 48%
DO8 genes
(30) +
GWAS
ALOX5AP rs10162089 13 31316738 non-coding INTRON Candidate 0.005861 1.93 56% 40%
Genes (180)
MAGI2 rs16886004 7 78021500 non-coding INTRON GWAS, 0.030517 2.04 19% 10%
Additive
HLA-DO8/ rs1894408 6 32786833 non-coding — Candidate 0.08935 1.50 39% 30%
TAP2 Genes (30)
HLA-DRA/ rs3135391 6 32410987 Synon EXON Candidate 0.060413 0.58 18% 27%
DRB1*1501 T118T variants
SLC1A4 rs759458 2 65245365 Nonsynon EXON GWAS, 4.44E−05 3.31 38% 16%
V101I Additive,
Extreme
Additive Model, Extreme Phenotype
Forte cohort Combined cohort
Al- Al-
Armit- Odds Al- lele Armit- Odds Al- lele
age Ratio lele Freq. age Ratio lele Freq.
P- (Regres- Freq. (Non- P- (Regres- Freq. (Non-
Gene(s) value sion) (Resp.) Resp.) value sion) (Resp.) Resp.)
ZAK/ 0.012992 0.00 0% 3% 1.32E−03 0.07 0% 4%
CDCA7
UVRAG 3.36E−05 0.12 3% 17% 9.09E−07 0.17 3% 14%
PTPKT 0.157158 0.36 2% 6% 0.005127 0.22 1% 5%
MBP 0.035452 0.53 29% 43% 0.00926 0.63 32% 43%
RFPL3/ 0.115337 Inf. 3% 0% 0.002785 Inf. 4% 0%
SLCSA4
region
HLA-DQ82/ 0.009234 0.45 37% 54% 1.17E−03 0.54 37% 50%
DO8
ALOX5AP 0.005285 2.32 48% 26% 0.00094 1.78 50% 36%
MAGI2 9.21E−03 3.64 20% 7% 6.08E−04 2.48 20% 9%
HLA-DO8/ 0.002633 2.85 42% 23% 1.15E−03 1.86 41% 28%
TAP2
HLA-DRA/ 0.027901 0.50 20% 33% 0.006382 0.57 19% 29%
DRB1*1501
SLC1A4 0.048948 1.86 38% 23% 2.92E−03 2.64 38% 18%
Additive Model, Extreme Phenotype
DD Dd dd
DD (Non- Dd (Non- dd (Non-
Gene(s) (Resp.) Resp.) (Resp.) Resp.) (Resp.) Resp.)
ZAK/ 0 0 1 10 154 111
CDCA7
UVRAG 0 1 9 32 145 88
PTPKT 0 0 4 13 151 108
MBP 16 22 67 60 71 39
RFPL3/ 0 0 11 0 144 171
SLCSA4
region
HLA-DQ82/ 17 26 79 69 57 26
DO8
ALOX5AP 43 14 69 57 42 48
MAGI2 4 2 53 18 98 100
HLA-DO8/ 22 10 81 47 50 64
TAP2
HLA-DRA/ 6 9 47 52 102 60
DRB1*1501
SLC1A4 20 3 71 37 63 81
TABLE 33
Allelic Model Characteristics of Individual SNPs in Model
Allelic Model
GALA cohort
Fisher Odds
Exact Ratio
Posi- Muta- Loca- P- (Minor
Gene(s) Name Chr tion tion tions Source value Allele) (95% CI)
ZAK/ kgp24415534 2 174156875 non-coding — GWAS, 6.03E−05 0.05 0.01 0.37
CDCA7 Additive
UVRAG kgp6214351 11 75546691 non-coding INTRON GWAS, 0.004741 0.42 0.23 0.77
Additive,
Extreme
PTPKT kgp6599438 20 40843626 non-coding INTRON Candidate 0.006974 0.21 0.07 0.68
Genes (180)
MBP kgp7747883 18 74804250 non-coding INTRON Candidate 0.042737 0.70 0.51 0.96
Genes (30)
RFPL3/ kgp8110667 22 32716792 non-coding — GWAS, 0.004709 Inf. — —
SLCSA4 Additive
region
HLA-DQ82/ kgp8817856 6 32744440 non-coding — Candidate 0.00202 0.59 0.43 0.82
DO8 genes
(30) +
GWAS
ALOX5AP rs10162089 13 31316738 non-coding INTRON Candidate 0.008386 1.56 1.12 2.16
Genes (180)
MAGI2 rs16886004 7 78021500 non-coding INTRON GWAS, 0.003923 2.01 1.25 3.24
Additive
HLA-DO8/ rs1894408 6 32786833 non-coding — Candidate 0.005009 1.64 1.17 2.31
TAP2 Genes (30)
HLA-DRA/ rs3135391 6 32410987 Synon EXON Candidate 0.041273 0.66 0.45 0.98
DRB1*1501 T118T variants
SLC1A4 rs759458 2 65245365 Nonsynon EXON GWAS, 0.000762 1.94 1.31 2.86
V101I Additive,
Extreme
Allelic Model
Forte cohort Combined cohort
Fisher Odds Fisher Odds
Exact Ratio Exact Ratio
P- (Minor P- (Minor
Gene(s) value Allele) (95% CI) value Allele) (95% CI)
ZAK/ 0.028468 0.15 0.03 0.82 2.28E−06 0.08 0.02 0.28
CDCA7
UVRAG 0.001081 0.29 0.14 0.60 1.60E−05 0.36 0.23 0.57
PTPKT 0.025262 0.29 0.10 0.85 0.000764 0.27 0.13 0.57
MBP 0.012876 0.59 0.39 0.89 0.001016 0.65 0.51 0.84
RFPL3/ 0.006157 Inf. — — 7.05E−06 Inf. — —
SLCSA4
region
HLA-DQ82/ 0.000595 0.48 0.32 0.73 1.75E−05 0.58 0.45 0.74
DO8
ALOX5AP 0.028565 1.60 1.05 2.45 0.001361 1.52 1.18 1.96
MAGI2 3.71E−05 4.80 2.04 11.31 1.41E−06 2.53 1.68 3.79
HLA-DO8/ 0.010522 1.78 1.14 2.77 1.75E−04 1.67 1.28 2.18
TAP2
HLA-DRA/ 0.056736 0.64 0.41 1.00 0.001498 0.70 0.52 0.93
DRB1*1501
SLC1A4 0.492021 1.18 0.75 1.88 0.001627 1.60 1.19 2.16
Allelic Model
D d
D (Non- d (Non-
Gene(s) (Resp.) Resp.) (Resp.) Resp.)
ZAK/ 3 16 795 346
CDCA7
UVRAG 37 43 759 319
PTPKT 11 18 783 344
MBP 267 158 529 204
RFPL3/ 32 0 764 362
SLCSA4
region
HLA-DQ82/ 308 191 478 171
DO8
ALOX5AP 382 136 410 222
MAGI2 159 32 639 326
HLA-DO8/ 327 106 485 252
TAP2
HLA-DRA/ 162 97 636 265
DRB1*1501
SLC1A4 235 75 561 287
Allelic Model, Extreme Phenotype
GALA cohort
Fisher Odds
Exact Ratio
Posi- Muta- Loca- P- (Minor
Gene(s) Name Chr tion tion tion Source value Allele) (95% CI)
ZAK/ kgp24415534 2 174156875 non-coding — GWAS, 0.08289 0.16 0.02 1.27
CDCA7 Additive
UVRAG kgp6214351 11 75546691 non-coding INTRON GWAS, 0.003078 0.21 0.07 0.63
Additive,
Extreme
PTPKT kgp6599438 20 40843626 non-coding INTRON Candidate 0.00588 0.00 — —
Genes (180)
MBP kgp7747883 18 74804250 non-coding INTRON Candidate 0.288087 0.76 0.48 1.21
Genes (30)
RFPL3/ kgp8110667 22 32716792 non-coding — GWAS, 0.014777 Inf. — —
SLCSA4 Additive
region
HLA-DQ82/ kgp8817856 6 32744440 non-coding — Candidate 0.060533 0.63 0.39 1.00
DO8 genes
(30) +
GWAS
ALOX5AP rs10162089 13 31316738 non-coding INTRON Candidate 0.007258 1.91 1.21 3.05
Genes (180)
MAGI2 rs16886004 7 78021500 non-coding INTRON GWAS, 0.029731 2.10 1.08 4.08
Additive
HLA-DO8/ rs1894408 6 32786833 non-coding — Candidate 0.086712 1.53 0.95 2.48
TAP2 Genes (30)
HLA-DRA/ rs3135391 6 32410987 Synon T118T EXON Candidate 0.075291 0.59 0.34 1.03
DRB1*1501 variants
SLC1A4 rs759458 2 65245365 Nonsynon EXON GWAS, 8.18E−05 2.97 1.72 5.12
V101I Additive,
Extreme
Allelic Model, Extreme Phenotype
Forte cohort Combined cohort
Fisher Odds Fisher Odds
Exact Ratio Exact Ratio
P- (Minor P- (Minor
Gene(s) value Allele) (95% CI) value Allele) (95% CI)
ZAK/ 0.078849 0.00 — — 1.58E−03 0.08 0.01 0.59
CDCA7
UVRAG 0.000229 0.14 0.05 0.42 1.51E−06 0.18 0.09 0.39
PTPKT 0.228331 0.38 0.09 1.56 0.010717 0.23 0.07 0.72
MBP 0.050093 0.54 0.31 0.97 0.009895 0.63 0.44 0.89
RFPL3/ 0.188468 Inf. — — 0.003203 Inf. — —
SLCSA4
region
HLA-DQ82/ 0.015048 0.49 0.28 0.86 2.35E−03 0.59 0.41 0.81
DO8
ALOX5AP 0.003862 2.46 1.34 4.54 0.000689 1.82 1.29 2.58
MAGI2 1.30E−02 3.30 1.24 8.78 7.06E−04 2.43 1.44 4.08
HLA-DO8/ 0.005246 2.45 1.30 4.61 1.58E−03 1.80 1.26 2.59
TAP2
HLA-DRA/ 0.031154 0.50 0.27 0.93 0.008266 0.58 0.39 0.88
DRB1*1501
SLC1A4 0.049785 1.93 1.02 3.85 2.38E−06 2.61 1.74 3.90
Allelic Model, Extreme Phenotype
D d
D (Non- d (Non-
Gene(s) (Resp.) Resp.) (Resp.) Resp.)
ZAK/ 1 10 309 232
CDCA7
UVRAG 9 34 299 208
PTPKT 4 13 306 229
MBP 99 104 209 138
RFPL3/ 11 0 299 242
SLCSA4
region
HLA-DQ82/ 113 121 193 121
DO8
ALOX5AP 155 85 153 153
MAGI2 61 22 249 218
HLA-DO8/ 125 67 181 175
TAP2
HLA-DRA/ 59 70 251 172
DRB1*1501
SLC1A4 111 43 197 199
Example 17 Preliminary Predictive Model: Clinical and Genetic Factors Combined A predictive model was generated based on the 11 SNPs shown in tables 32 and 33 and the two Clinical co-variants shown in table 23.
Receiver Operating Characteristic (ROC) analysis was performed using the actual value (case or control) and predicted value for each sample from the multi-marker regression model (FIG. 1). For these preliminary analyses, two risk groups were defined using the predicted values from the multi-marker regression model. The predictive threshold value was set at 0.71 (termed “model 3”) based on a variety of factors after consultation with the Teva team and Teva MS clinical experts.
Ultimately, a threshold that best differentiated between responders and non-responders (minimum positive predictive value of 90% or higher) (FIG. 2), while maximizing the number of predicted responders (predicted responders >60%) (FIG. 3) was selected. This threshold also coincided with the lowest p-value of all the thresholds examined (Chi square p-value 6.1×10−46, odds ratio 19.9) (FIG. 4). The positive predictive value (% of all predicted responders to be true responders) was 91.1%, sensitivity (% of all true responders detected) was 80.2%; specificity (% of all true non-responders classified as non-responders) was 83.1%; and the negative predictive value (% of all true non-responders classified as non-responders) was 65.9%.
Example 18 Patient Responses Predicted by the Preliminary Predictive Model For the genotyped patients of the GALA and FORTE cohorts, based on the predictive model, 60% of patients were classified as “predicted responders” with a response rate of 91.1% (as defined by the a priori definition of responders and non-responders). While 40% of patients were classified as “predicted non-responders” with an overall response rate of 34% (FIG. 5).
Compared to the “predicted non-responders”, the “predicted responders” exhibited a 2.7-fold improved response rate (91% vs. 34%) (P<10−40); and the “predicted responders” had a 34% improvement in response rate compared to the overall cohort (68% vs. 91%).
The annualized relapse rate (ARR) of the “predicted responders” (0.21±0.03 standard error of the mean) was reduced (improved) by 60% compared to the overall patient cohort (0.53±0.04), and reduced (improved) by 80% compared to the “predicted non-responders” (1.04±0.08) (p-value 2.2×10−25).
The number of confirmed relapses (nrelapse) of the “predicted responders” (0.19±0.03 standard error of the mean) was reduced (improved) by 58% compared to the overall patient cohort (0.46±0.03), and reduced (improved) by 78% compared to the “predicted non-responders” (0.88±0.06) (p-value 7.70×10−32).
The number of T1 enhancing lesions at month 12 was significantly reduced (improved) by 47% in the “predicted responders” compared to the “predicted non-responders” (0.91±0.18 versus 1.70±0.38; p-value 0.043). Similarly, EDSS progression was significantly delayed (improved) by 72% in the “predicted responders” versus the “predicted non-responders” (0.03±0.01 vs. 0.10±0.02; p-value 0.00095), and showed a strong trend with a 49% reduced progression compared to the overall cohort (value 0.057, p-value 0.08).
Predictive Modeling A predictive model based on the identified markers was developed and tested in the full cohorts, including intermediate responders. Additional independent cohorts are used to evaluate and confirm the predictive model.
DNA was collected from consenting RPMS patients in one year GALA study (40 mg Copaxone TIW, or placebo) and one year FORTE study (20 mg Copaxone or 40 mg Copaxone daily) (“PGx population”) (Table 34) The PGx (i.e. the population studied for genetic analyses) and ITT (intent to treat) populations did not differ on baseline characteristics.
To identify genetic markers associated with high response to Copaxone® comprising the following characteristics: (1) high response as measured by ARR reductions, (2) predictive, not prognostic, markers: associated with response only in Copaxone®-treated patients, and not in the placebo group, (3) markers that are confirmed in an independent cohort, and (4) a subset of GALA and FORTE studies' patients with clarly defined response phenotypes (high responders versus low responders) (FIG. 6) Patient DNA samples were genotyped for 4.3 million genetic variants (Illumina HumanOmni5 array).
Association analysis, using a tiered candidate-marker and genome-wide approach, was conducted in the GALA cohort to identify GA-specific response-associated SNPs. SNPs that were not associated with placebo response and that replicated in the FORTE cohort, were selected for modeling.
Regression analysis was applied, with the threshold for distinguishing responders from non-responders was selected by analysis of receiver-operator curves. Intermediate responders were genotyped by either Illumina 5M array or focused taqman-based SNP genotyping and Sanger sequencing.
The SNP-signature was evaluated in the full GALA/FORTE population including intermediate patients (FIG. 7). In the high reponse/low response subgroups of both GALA and FORTE, the SNP signature exhibited highly predictive characteristics (OR 6 to 8, p-value<10−11) (Table 35). Validation of the identified model can be applied to additional independent cohorts.
The signature was associated with Copaxone®-, and not placebo-response since 129 placebo-treated patients were predicted to be high Copaxone®-responders based on the signature. These patients of not show ARR reduction when treated with placebo (3% ARR reduction versus remaining placebo patients who provided DNA samples (n=252)) The SNP signature was significantly associated with high response to Copaxone in both GALA and FORTE (OR of 1.9 to 3.8, p<0.002 including sensitivity analysis) and not in placebo (OR of 0.9 to 1.2, NS). Genetic association with response to Copaxone®, and not placebo, was identified. In Copaxone® naïve RRMS patients, the 11 SNP signature identifies high Copaxonec responders who exhibit significantly greater reductions in ARR compared to the average response observed in Copaxone® clinical trials.
TABLE 34
Baseline characteristics of PGx and ITT populations
Study GALA FORTE
Population ITT PGx ITT PGx
N 1404 1156 (82%) 1155 504 (52%)
Age (Ave ± SD) 37.6 ± 9.35 37.71 ± 9.38 36.27 ± 8.99 35.97 ± 8.82
Gender (% Female) 67.90% 67.90% 71.70% 72.20%
Caucasian 97.60% 97.90% 95.20% 100%
Disease duration (years) 3.76 ± 4.9 3.74 ± 4.94 3.16 ± 4.41 2.86 ± 4.05
No. of Relapses in the Last 2 Years 1.91 ± 0.91 1.89 ± 0.92 2.01 ± 1.00 1.97 ± 0.89
Baseline EDSS 2.79 ± 1.23 2.77 ± 1.21 2.12 ± 1.12 2.13 ± 1.12
TABLE 35
Genes of the 11 SNP Signature
GALA FORTE
GA-treated GA-treated
Genes of 11-SNP Signature * OR OR
HLA-DRB1*15:01 0.7 0.6
HLA gene region 1.7 1.8
Myelin basic protein gene 0.7 0.6
Receptor-tyrosine protein 0.2 0.3
phosphatase gene
Arachidonate 1.6 1.6
5-lipoxygenase-activating protein
Membrane-associated guanvlate kinase gene 2.2 5.6
Solute carrier family 5 (low affinity Inf. Inf.
glucose co-transporter) gene
HLA gene region 0.5 0.5
Mitogen-activated protein kinase gene region 0.05 0.1
Radiation resistance-associated gene protein 0.2 0.1
Glutamate/neutral amino acid transporter 3.3 1.9
* All SNPs met statistical significance
Example 19 Additional genotyping of the 11 SNPs of the predictive model (rs3135391, rs1894408, kgp7747883, kpg6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351, rs759458) was conducted on the remaining portion of the patients from the GALA and FORTE cohorts, for which DNA was available (FIG. 8).
When analysis was conducted for all genotyped patients of the GALA and FORTE cohorts, based on the predictive model (11 SNPs and 2 clinical variables), 34% of GALA, and 42% of FORTE-patients were classified as “predicted responders”.
In the GALA Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” (0.18510.032 standard error of the mean) was reduced (improved) by 51% compared to the “predicted non-responders” (0.374±0.038) (p-value=0.0028) and by 64% compared to the placebo (0.510±0.062) (p-value<0.0001).
In the FORTE Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” (0.102±0.020 standard error of the mean) was reduced (improved) by 72% compared to the “predicted non-responders” (0.36810.039) (p-value<0.0001).
Example 20 Analysis was conducted for all genotyped patients of the GALA and FORTE cohorts, based on the 11 SNPs in the predictive model, but without including the clinical variables, and using a threshold at ˜30% of the population classified as “predicted responders” (FIG. 9).
In the GALA Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” (0.131±0.026 standard error of the mean) was reduced (improved) by 62% compared to the “predicted non-responders” (0.382±0.037) (p-value<0.0001) and by 71% compared to the placebo (0.488±0.058) (p-value<0.0001).
In the FORTE Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” (0.145±0.029 standard error of the mean) was reduced (improved) by 50% compared to the “predicted non-responders” (0.29010.03) (p-value=0.0113).
Example 21 Additional genotyping of 10 SNPs of the predictive model (rs3135391, rs1894408, kpg6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351 and rs759458) was conducted on the remaining portion of the patients from the GALA and FORTE cohorts, for which DNA was available.
When analysis was conducted for all genotyped patients of the GALA and FORTE cohorts, based on the 10 SNPs and 2 clinical variables, 34% of GALA, and 42% of FORTE-patients were classified as “predicted responders”.
In the GALA Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” (0.185±0.032 standard error of the mean) was reduced (improved) by 51% compared to the “predicted non-responders”(0.374±0.038) (p-value-0.0028) and by 64% compared to the placebo (0.510±0.062) (p-value<0.0001).
In the FORTE Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” (0.102±0.020 standard error of the mean) was reduced (improved) by 72% compared to the “predicted non-responders” (0.368±0.039) (p-value<0.0001).
Example 22 Additional genotyping of the 11 SNPs of the predictive model (rs3135391, rs1894408, kgp7747883, kpg6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351, rs759458) was conducted on the remaining portion of the patients from the GALA and FORTE cohorts, for which DNA was available (FIG. 10).
When analysis was conducted for all genotyped patients of the GALA and FORTE cohorts, based on the predictive model (11 SNPs) 31% of GALA, and 25-35% of FORTE-patients were classified as “predicted responders”.
In the GALA Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” (mean=0.135, 95% CI [0.096, 0.190])—was reduced (improved) by 61% (95% CI [44%, 72%], p<0.0001) compared to the “predicted non-responders” (mean=0.345, 95% CI (0.284, 0.418)).
In the FORTE Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” was reduced (improved) by 30-40% compared to the “predicted non-responders”.
Example 23 Additional genotyping of the 10 SNPs of the predictive model (rs1894408, kgp7747883, kpg6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351, rs759458) was conducted on the remaining portion of the patients from the GALA and FORTE cohorts, for which DNA was available (FIG. 11).
When analysis was conducted for all genotyped patients of the Gala and FORTE cohorts, based on the predictive model (10 SNPs), 31% of GALA, and 25-35% of FORTE-patients were classified as “predicted responders”.
In the GALA Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” (mean-0.133, 95% CI [0.094, 0.187]) was reduced (improved) by 61% (95% CI [44%, 73%], p<0.0001) compared to the “predicted non-responders” (mean-0.345, 95% CI [0.285, 0.418]).
In the FORTE Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” was reduced (improved) by 30-40% compared to the “predicted non-responders”.
Example 24 Additional genotyping of the 9 SNPs of the predictive model (kgp7747883, kpg6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351, rs759458) was conducted on the remaining portion of the patients from the GALA and FORTE cohorts, for which DNA was available (FIG. 12).
When analysis was conducted for all genotyped patients of the GALA and FORTE cohorts, based on the predictive model (9 SNPs), 34% of GALA, and 25-35% of FORTE-patients were classified as “predicted responders”.
In the GALA Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” (mean=0.146, 95% CI [0.107, 0.200]) was reduced (improved) by 57% (95% CI [40%, 70%], p<0.0001) compared to the “predicted non-responders” (mean-0.344, 95% CI [0.283, 0.418])
In the FORTE Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” was reduced (improved) by 40-70% compared to the “predicted non-responders”.
Example 25 Additional genotyping of the 10 SNPs of the predictive model (rs1894408, kgp7747883, kpg6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351, rs759458) was conducted on the remaining portion of the patients from the GALA and FORTE cohorts, for which DNA was available (FIG. 13).
When analysis was conducted for all genotyped patients of the GALA and FORTE cohorts, based on the predictive model (10 SNPs), about 30% (20-40%) of GALA, and about 30% (20-40%) of FORTE-patients were classified as “predicted responders”.
In the GALA Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” was reduced (improved) by (30-40%) compared to the “predicted non-responders” and by 55%-65% compared to the placebo (0.510±0.062).
In the FORTE Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” was reduced (improved) by 30-40% compared to the “predicted non-responders”.
Example 26 Additional genotyping of the 9 SNPs of the predictive model (kgp7747883, kpg6599438, rs10162089, rs16886004, kgp8110667, kgp8817856, kgp24415534, kgp6214351, rs759458) was conducted on the remaining portion of the patients from the GALA and FORTE cohorts, for which DNA was available (FIG. 14).
When analysis was conducted for all genotyped patients of the GALA and FORTE cohorts, based on the predictive model (10 SNPs), about 30% (20-40%) of GALA, and about 30% (20-40%) of FORTE-patients were classified as “predicted responders”.
In the GALA Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” was reduced (improved) by (30-40%) compared to the “predicted non-responders” and by 55%-65% compared to the placebo (0.510±0.062).
In the FORTE Copaxone treated patients, the annualized relapse rate (ARR) of the “predicted responders” was reduced (improved) by 30-40% compared to the “predicted non-responders”.
Biology of High Response to Copaxone® Identified genes are associated with Copaxone® (glatiramer acetate, or GA) mechanism of action. These genes include: (1) Myelin Basic Protein (MBP), which is associated with Copaxone® response (38), and Copaxone® designed to mimic MBP; (2) MHC region (3 SNPs), including HLA-DRB1*15:01 (37) involved in antigen processing and presentation and is associated with Copaxone® response and MS susceptibility or severity; and (3) arachidonate 5-lipoxygenase-activating protein, involved in synthesis of leukotrienes (inflammation) and associated with Copaxone® response (40).
Identified genes are also associated with MS severity and/or the brain. These genes include: (1) Membrane-associated guanylate kinase, a synaptic junction scaffold molecule exclusively expressed in brain and shown to modulate MS severity; (2) Glutamate/neutral amino acid transporter, which transports glutamate and alanine (2 of the 4 amino acid components of Copaxone®), as well as serine, cysteine, and threonine and has highest expression in brain; (3) Radiation resistance-associated gene protein, which is highly expressed in brain and has a role in axis formation and autophagy; and (4) Receptor-tyrosine protein phosphatase, associated with Copaxone® response, and tyrosine phosphorylation involved in myelin formation, differentiation of oligodendrocytes and Schwann cells, and recovery from demyelinating lesions.
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